Glycine derivatives

ABSTRACT

The present invention relates to novel positive inotropic and lusitropic 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one derivatives having positive inotropic and lusitropic properties which are useful in the treatment of warm-blooded animals suffering from Congestive Heart Failure. Pharmaceutical compositions containing said compounds as an active ingredient. Methods of preparing said compounds and pharmaceutical compositions.

This application is a division of application Ser. No. 735,229, filedJul. 24, 1991, now U.S. Pat. No. 5,120,845, which was a division ofapplication Ser. No. 615,748, filed on Nov. 16, 1990, now U.S. Pat. No.5,043,327, which was a continuation-in-part of application Ser. No.529,826, filed May 29, 1990, now abandoned, which was acontinuation-in-part of application Ser. No. 463,922, filed Jan. 9,1990, now abandoned, which in turn was a continuation-in-part ofapplication Ser. No. 381,338, filed Jul. 18, 1989, now abandoned.

BACKGROUND OF THE INVENTION

In EP-A-O,116,948, EP-A-O,153,152 and in U.S. Pat. Nos. 4,593,029 and4,670,434 there are described a number of imidazo[2,1-b]quinazolinonesas phosphodiesterase inhibitors having positive inotropic properties.Analogous compounds are also disclosed in J. Med. Chem., 30, pp. 303-318(1987) and 31, pp. 145-152 (1988).

DESCRIPTION OF THE INVENTION

The present invention is concerned with novel3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one derivatives having theformula ##STR1## the pharmaceutically acceptable addition salts thereofand the stereochemically isomeric forms thereof, wherein

R is hydrogen, C₁₋₆ alkyl, phenyl optionally substituted with from 1 to3 substituents each independently selected from halo, hydroxy, C₁₋₆alkyloxy, C₁₋₆ alkyl or trifluoromethyl; pyridinyl; or thienyloptionally substituted with halo or C₁₋₆ alkyl;

R¹ is hydrogen or C₁₋₆ alkyl;

R² is hydrogen, C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl or phenyl; or

R¹ and R² taken together may also form a C₁₋₅ alkanediyl radical;

X is a radical of formula

    ═O                                                     (a),

    ═N--O--R.sup.3                                         (b),

or

    ═CH--R.sup.4                                           (c);

R³ is hydrogen, tri(C₁₋₆ alkyl)silyl or C₁₋₆ alkyl optionallysubstituted with COOH, COOC₁₋₄ alkyl, CONR⁵ R⁶ or COOCH₂ CONR⁷ R⁸ ;

R⁴ is COOH, COOC₁₋₄ alkyl, CONR⁵ R⁶, COOCH₂ CONR⁷ R⁸ or C₁₋₆ alkyloptionally substituted with COOH, COOC₁₋₄ alkyl, CONR⁵ R⁶ or COOCH₂CONR⁷ R⁸ ;

R⁵ is hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl, C₁₋₄ alkyloxyC₁₋₄ alkyl,hydroxycarbonylC₁₋₄ alkyl, C₁₋₄ alkyloxycarbonylC₁₋₄ alkyl;

R⁶ is hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl or C₃₋₇ cycloalkyl; or

R⁵ and R⁶ taken together with the nitrogen atom to which they areattached may form a pyrrolidinyl, morpholinyl or piperazinyl ring, saidpiperazinyl ring being optionally substituted on the nitrogen atom withC₁₋₄ alkyl or hydroxyC₁₋₄ alkyl; and

R⁷ and R⁸ each independently are hydrogen, C₁₋₄ alkyl or hydroxyC₁₋₄alkyl.

In the foregoing definitions the term halo defines fluoro, chloro, bromoand iodo; C₁₋₄ alkyl defines straight and branched saturated hydrocarbonradicals having from 1 to 4 carbon atoms, such as, for example, methyl,ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and1,1-dimethylethyl; C₁₋₆ alkyl defines C₁₋₄ alkyl and the higher homologsthereof such as, for example, pentyl, hexyl and the like; C₃₋₇cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl; C₁₋₅ alkanediyl defines straight and branch chainedbivalent hydrocarbon radicals having from 1 to 5 carbon atoms such as,for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, 1,1-ethanediyl, 1,1-propanediyl, 1,2-propanediyl andthe like. Tri(C₁₋₆ alkyl)silyl in particular may be trimethylsilyl,triethylsilyl, tert.butyldimethylsilyl and the like.

Pharmaceutically acceptable addition salts as mentioned hereinabovecomprise the therapeutically active non-toxic addition salt forms whichthe compounds of formula (I) are able to form. Said salt forms canconveniently be obtained by treating the base form of the compounds offormula (I) with appropriate acids such as inorganic acids, for example,hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids,sulfuric acid, nitric acid, phosphoric acid and the like; or organicacids, such as, for example, acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic,butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

The compounds of formula (I) containing acidic protons may also beconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts, the alkali and earth alkaline metal salts, e.g. the lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabaminesalts, and salts with amino acids such as, for example, arginine, lysineand the like.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The compounds of this invention may have several asymmetric carbon atomsin their structure. Each of these chiral centers may be indicated by thestereochemical descriptors R and S. The compounds of formula (I) whereinX is a radical of formula (b) or (c) may occur as mixtures of E- andZ-forms or as pure E-forms or pure Z-forms. This R and S notation and Eand Z notation corresponds to the rules described in Pure Appl. Chem.,1976, 45, 11-30.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereoisomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g. counter current distribution,liquid chromatography and the like; and enantiomers may be separatedfrom each other following art-known resolution methods, for example, bythe selective crystallization of their diastereomeric salts with chiralacids. Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reactions occurstereospecifically. Preferably, if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials. Stereochemically isomeric forms of thecompounds of formula (I) are obviously intended to be included withinthe scope of the invention.

A first group of interesting compounds are those compounds of formula(I) wherein R² is hydrogen, C₁₋₆ alkyl or hydroxyC₁₋₆ alkyl; and/or R¹and R² taken together may also form a C₁₋₅ alkanediyl radical; and/or Ris phenyl optionally substituted with from 1 to 3 substituents eachindependently selected from halo, hydroxy, C₁₋₆ alkyloxy, C₁₋₆ alkyl ortrifluoromethyl.

A second group of interesting compounds are those compounds of formula(I) wherein R² is hydrogen, C₁₋₆ alkyl or hydroxyC₁₋₆ alkyl; and/or R¹and R² taken together may also form a C₁₋₅ alkanediyl radical; and/or Ris hydrogen, C₁₋₆ alkyl or pyridinyl.

A third group of interesting compounds are those compounds of formula(I) wherein R² is hydrogen, C₁₋₆ alkyl or hydroxyC₁₋₆ alkyl; and/or R¹and R² taken together may also form a C₁₋₅ alkanediyl radical; and/or Ris thienyl.

More interesting compounds are those interesting compounds wherein R¹ ishydrogen; and/or R² is hydrogen or C₁₋₆ alkyl; and/or R is phenyloptionally substituted with halo, C₁₋₆ alkyloxy or C₁₋₆ alkyl; and/or Xis a radical of formula (a), (b) or (c); and/or R⁵ is hydrogen or C₁₋₄alkyl; and/or R⁶ is C₁₋₄ alkyl or C₃₋₇ cycloalkyl.

Other more interesting compounds are those interesting compounds whereinR¹ is hydrogen; and/or R² is hydrogen or C₁₋₆ alkyl; and/or R ishydrogen, C₁₋₆ alkyl or pyridinyl; and/or X is a radical of formula (a),(b) or (c); and/or R⁵ is hydrogen or C₁₋₄ alkyl; and/or R⁶ is C₁₋₄ alkylor C₃₋₇ cycloalkyl.

Still other more interesting compounds are those interesting compoundswherein R¹ is hydrogen; and/or R² is hydrogen or C₁₋₆ alkyl; and/or R isthienyl; and/or X is a radical of formula (a), (b) or (c); and/or R⁵ ishydrogen or C₁₋₄ alkyl; and/or R⁶ is C₁₋₄ alkyl or C₃₋₇ cycloalkyl.

Particularly interesting compounds are those interesting compoundswherein R¹ and R² are hydrogen; and/or R is phenyl optionallysubstituted with fluoro, chloro, bromo, methoxy or methyl; and/or X is aradical of formula (a), (b) or (c); and/or R³ is hydrogen, C₁₋₄ alkylsubstituted with COOC₁₋₄ alkyl or with CONR⁵ R⁶, R⁵ being C₁₋₄ alkyl andR⁶ being C₅₋₇ cycloalkyl; and/or R⁴ is COOH, COOC₁₋₄ alkyl or CONR⁵ R⁶,R⁵ being C₁₋₄ alkyl and R⁶ being C₅₋₇ cycloalkyl.

Other particularly interesting compounds are those interesting compoundswherein R¹ and R² are hydrogen; and/or R is hydrogen, C₁₋₄ alkyl orpyridinyl; and/or X is a radical of formula (a), (b) or (c); and/or R³is hydrogen, C₁₋₄ alkyl substituted with COOC₁₋₄ alkyl or with CONR⁵ R⁶,R⁵ being C₁₋₄ alkyl and R⁶ being C₅₋₇ cycloalkyl; and/or R⁴ is COOH,COOC₁₋₄ alkyl or CONR⁵ R⁶, R⁵ being C₁₋₄ alkyl and R⁶ being C₅₋₇cycloalkyl.

Still other particularly interesting compounds are those interestingcompounds wherein R¹ and R² are hydrogen; and/or R is thienyl; and/or Xis a radical of formula (a), (b) or (c); and/or R³ is hydrogen, C₁₋₄alkyl substituted with COOC₁₋₄ alkyl or with CONR⁵ R⁶, R⁵ being C₁₋₄alkyl and R⁶ being C₅₋₇ cycloalkyl; and/or R⁴ is COOH, COOC₁₋₄ alkyl orCONR⁵ R⁶, R⁵ being C₁₋₄ alkyl and R⁶ being C₅₋₇ cycloalkyl.

The most interesting compounds within the present invention are:

(E+Z)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2(1H)-one,

(E)-N-cyclohexyl-N-methyl-2-[[[phenyl-(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]-quinazolin-7-yl)methylene]oxy]acetamide,

(E)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2(1H)-one,

(E)-N-cyclohexyl-N-methyl-2-[[[(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]acetamideand

(E+Z)-N-cyclohexyl-N-methyl-2-[[[(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)(2-thienyl)methylene]amino]oxy]acetamide,the pharmaceutically acceptable addition salts and the stereochemicallyisomeric forms thereof.

In order to simplify the structural representation of the compounds andof some of the intermediates in the following preparations, the3,5-dihydro-imidazo[2,1-b]quinazolin-2(1H)-one moiety will hereinafterbe represented by the symbol D. ##STR2##

The compounds of formula (I) can generally be prepared by cyclizing anintermediate of formula (II) with a reagent of formula (III) wherein W¹represents a leaving group such as, for example, trihalomethyl, e.g.trichloromethyl or a halide, in particular bromide, in a suitablesolvent. ##STR3##

In formulae (II) and (IV) L represents a reactive leaving group such as,for example, C₁₋₆ alkyloxy, phenyloxy, hydroxy, amino, imidazolyl andthe like. Suitable solvents for said cyclization are, for example,water; aromatic hydrocarbons, e.g. benzene, methylbenzene,dimethylbenzene and the like; alcohols, e.g. methanol, ethanol,1-propanol, 2-propanol, 1-butanol and the like, diols, e.g.1,2-ethanediol and the like; dipolar aprotic solvents, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphortriamide and the like; ethers, e.g. tetrahydrofuran, 1,1'-oxybisethane,1,4-dioxane and the like; halogenated hydrocarbons, e.g.trichloromethane, tetrachloromethane and the like; and mixtures thereof.The reaction can conveniently be conducted by stirring the reactantsinitially at a low temperature such as between -10° C. and 5° C. andthen at room temperature. In some instances the intermediate guanidineof formula (IV) may be isolated at this stage. In order to enhance thereaction rate of the second cyclization step it may be appropriate toheat the reaction mixture at an elevated temperature, in particular atthe reflux temperature of the reaction mixture.

The compounds of formula (I) may also be obtained by cyclizing anintermediate of formula (II) withN-cyanoimido-S,S-dimethyldithiocarbonate or with an Q-alkylisourea orS-alkylisothiourea wherein R⁹ is alkyl, thus yielding respectively aN-cyanoguanidine of formula (IV-a) or a N-alkyloxycarbonyl guanidine offormula (IV-b). ##STR4##

The N-cyanoguanidine of formula (IV-a) may be converted into compoundsof formula (I) upon heating, preferably at the reflux temperature of thereaction mixture, in a suitable solvent such as an alkanol, e.g.ethanol, propanol, butanol and the like, and in the presence of an acidsuch as, for example, hydrochloric acid. The N-alkyloxycarbonylguanidine of formula (IV-b) in turn, may be converted into compounds offormula (I) by base hydrolysis of the carbamate and subsequentcyclization in the presence of an acid, optionally at an enhancedtemperature.

In all of the foregoing and in the following preparations, the reactionproducts may be isolated from the reaction mixture and, if necessary,further purified according to methodologies generally known in the art.

The compounds of formula (I) can also be prepared from a quinazolinederivative of formula (V) wherein L is a leaving group as definedhereinbefore and R⁹ is C₁₋₆ alkyl or aryl, ##STR5## by cyclization withammonia or a salt thereof such as, for example, an ammonium halide, e.g.ammonium chloride; ammonium carbonate; ammonium acetate and the likeammonium salts, in a suitable reaction-inert solvent such as, forexample, water, an alkanol, e.g. methanol, ethanol and the like, acarboxylic acid, e.g. acetic, propanoic acid and the like, or a mixtureof such solvents. In order to enhance the rate of the reaction, it maybe advantageous to heat the reaction mixture, in particular to thereflux temperature of the reaction mixture.

The compounds of formula (I) wherein X is a radical of formula (b), saidcompounds being represented by formula (I-b), can be obtained byreacting a compound of formula (I) wherein X is a radical of formula(a), said compound being represented by formula (I-a), with anappropriate hydroxylamine derivative of formula (VI) or an acid additionsalt thereof. ##STR6##

Said reaction can be carried out by stirring and heating the reagents inan appropriate solvent at an enhanced temperature, in particular thereflux temperature of the reaction mixture. Appropriate solvents are forexample, aromatic hydrocarbons, e.g. benzene, methylbenzene,dimethylbenzene and the like; halogenated hydrocarbons, e.g.trichloromethane, tetrachloromethane and the like; ethers, e.g.1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; dipolaraprotic solvents, e.g. N,N-dimethylformamide, N,N-dimethylacetamide,acetonitrile, pyridine and the like, or mixtures thereof.

The compounds of formula (I) wherein X is a radical of formula (c), saidcompounds being represented by formula (I-c), may be prepared byreacting the compounds of formula (I-a) with a phosphorus ylide offormula (VII) (Wittig reaction) or with an ylide of formula (VIII)prepared from a phosphonate (Horner-Emmons reaction). ##STR7## Informula (VIII) R" represents C₁₋₆ alkyl. The reaction can convenientlybe conducted by treating a phosphonium salt or a phosphonate with anappropriate base such as, for example, butyllithium, methyllithium,sodium amide, sodium hydride, a sodium or potassium alkoxide,sulfinylbis(methane) sodium salt and the like bases, under an inertatmosphere and in a reaction-inert solvent such as for example, ahydrocarbon, e.g. hexane, heptane, cyclohexane and the like; an ether,e.g. 1,1'oxybisethane, tetrahydrofuran, 1,2-dimethoxyethane and thelike; a dipolar aprotic solvent, e.g. dimethylsulfoxide,hexamethylphosphor triamide, and the like solvents; and subsequentlytreating the thus obtained ylides (VII) or (VIII) with the compound offormula (I-a), optionally at a slightly enhanced temperature.

Alternatively the compounds of formula (I-c) may be prepared by reactinga compound of formula (I-a) with an organometallic reagent of formula(IX) wherein M represents a metal group such as, for example, lithium,halomagnesium, copper lithium and the like; and subsequently dehydratingthe alcohol of formula (X), for example by treatment with an appropriateacid, e.g. hydrochloric or sulfuric acid in a solvent. ##STR8## Theorganometallic reagent may conveniently be prepared following art-knownmethods by reacting an appropriate halide with a metal such as lithiumor magnesium in a reaction-inert solvent such as, for example, an ether,e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,2-dimethoxyethane and thelike.

The compounds of formula (I-b) wherein R³ is other than hydrogen, saidradical being represented by formula R^(3-a) and said compounds byformula (I-b-1) can also be obtained from compounds of formula (I-b)wherein R³ is hydrogen, said compounds being represented by formula(I-b-2), by O-alkylation or O-silylation with an appropriate alkylatingor silylating reagent of formula R^(3-a) -W². ##STR9##

In said alkylating or silylating reagent, W² represents a leaving groupsuch as, for example, halo, e.g. chloro, bromo, iodo or sulfonyloxy,e.g. 4-methylbenzenesulfonyloxy, benzenesulfonyloxy,2-naphthalenesulfonyloxy, methanesulfonyloxy,trifluoromethanesulfonyloxy and the like leaving groups. SaidO-alkylation and O-silylation reaction can conveniently be conducted bystirring the reactants in a reaction-inert solvent in the presence of abase. Appropriate solvents are halogenated hydrocarbons such as, forexample, dichloromethane, trichloromethane and the like; etherts, e.g.1,1'-oxybisethane, tetrahydrofuran and the like; dipolar aproticsolvents, e.g. N,N-dimethylformamide, N,n-dimethylacetamide, pyridine,acetonitrile; and the like solvents. Suitable bases are tertiairy aminessuch as, for example, N,N-diethylethanamine, 4-methylmorpholine,pyridine, tetramethylguanidine and the like.

Furthermore, the compounds of formula (I-b-2) which may occur as E-orZ-forms, or mixtures thereof, may be isomerized by equilibration in anacidic medium. ##STR10##

The compounds of formula (I-b-1) wherein R^(3-a) is tri(C₁₋₆ alkyl)silylcan be desilylated to the oximes of formula (I-b) by treatment with afluoride salt such as, for example, potassium fluoride, tetrabutylammonium fluoride, or by reaction with hydrofluoric acid, in a solventsuch as, an ether, e.g. 1,1'-oxybisethane, tetrahydrofuran; or in anaqueous mixture thereof. As the compounds of formula (I-b-1) whereinR^(3-a) is tri(C₁₋₆ alkyl)silyl can easily be separated in the E- andZ-stereoisomers following art-known procedures such as selectivecrystallization and chromatography, and desilylated as describedhereinabove, this sequence provides an efficient procedure for preparingthose stereomers of (I-b) which can not be prepared by the isomerizationprocedure mentioned hereinabove.

The compounds of formula (I-b-1) wherein R^(3-a) is C₁₋₆ alkylsubstituted with COOH, COOC₁₋₆ alkyl, CONR⁵ R⁶ or COOCH₂ CONR⁷ R⁸ andthe compounds of formula (I-c) wherein R⁴ is COOH, COOC₁₋₄ alkyl, CONR⁵R⁶, COOCH₂ CONR⁷ R⁸ or C₁₋₆ alkyl substituted with COOH, COOC₁₋₄ alkyl,CONR⁵ R⁶ or COOCH₂ CONR⁷ R⁸ can be converted into each other followingart known procedures such as, for example, esterification, amidation,transesterification, transamidation, ester hydrolysis and the likemethods.

For example, the compounds wherein R^(3-a) or R⁴ is C₁₋₆ alkylsubstituted with COOH or R⁴ is COOH may be converted into an esterwherein R^(3-a) or R⁴ is C₁₋₄ alkyl substituted with COOC₁₋₄ alkyl orCOOCH₂ CONR⁷ R⁸, or R⁴ is COOC₁₋₄ alkyl or COOCH₂ CONR⁷ R⁸, or into anamide wherein R^(3-a) or R⁴ is C₁₋₆ alkyl substituted with CONR⁵ R⁶ orR⁴ is CONR⁵ R⁶ by treating the carboxylic acid with an alkanol offormula C₁₋₄ alkyl-OH or an alcohol of formula HOCH₂ CONR⁷ R⁸ or anamine of formula HNR⁵ R⁶ in the presence of a suitable reagent capableof forming esters and/or amides. Typical examples of such reagents arefor example, dicyclohexylcarbodiimide, 2-chloro1-methylpyridiniumiodide, phosphorus pentoxide, 1,1'-carbonylbis[1H-imidazole],1,1'-sulfonylbis[1H-imidazole] and the like reagents. Alternatively,said carboxylic acids may be converted into suitable reactive functionalderivatives thereof such as, for example, an acyl halide, symmetric ormixed anhydride, ester, amide, acyl azide, cyclic anhydride, lactone,lactam and the like derivatives before reaction with the alkanol C₁₋₄alkylOH, the alcohol of formula HOCH₂ CONR⁷ R⁸ or the amine HNR⁵ R⁶.Said reactive functional derivatives may be prepared following art knownmethods, for example, by reacting the carboxylic acid with ahalogenating reagent such as, for example, thionyl chloride, phosphoroustrichloride, polyphosphorous acid, phosphoryl chloride, oxalyl chlorideand the like, or by reacting said carboxylic acid with an acyl halidesuch as acetyl chloride and the like. Said reactive functionalderivatives of the carboxylic acids may be generated in situ, or ifdesired, be isolated and further purified before reacting them with thealkanol C₁₋₄ alkyl-OH, the alcohol of formula HOCH₂ CONR⁷ R⁸ or theamine HNR⁵ R⁶.

Said esterification and amidation reactions can conveniently be carriedout by stirring the reactants, optionally in a suitable reaction-inertsolvent such as, for example, a halogenated hydrocarbon, e.g.dichloromethane, trichloromethane and the like; an aromatic hydrocarbon,e.g. benzene, methylbenzene and the like; an ether, e.g.1,1'-oxybisethane, tetrahydrofuran and the like; or a dipolar aproticsolvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, pyridine andthe like. In some instances it may be appropriate to employ an excess ofone of the reagents as solvent. The water, acid, alcohol or amine whichis liberated during the course of the reaction may be removed from thereaction mixture by art-known procedures such as, for example,azeotropical distillation, complexation, salt formation and the likemethods. In some instances particularly the addition of a suitable basesuch as, for example, an amine, e.g. N,N-diethylethanamine,4-ethylmorpholine, pyridine or N,N-dimethyl-4-pyridinamine, may beappropriate. Further, in order to enhance the rate of the reaction, saidacylation reaction may advantageously be conducted at a somewhatelevated temperature, in particular the reflux temperature of thereaction mixture.

Transesterification may be accomplished by reacting a compound whereinR^(3-a) or R⁴ is C₁₋₆ alkyl substituted with COOC₁₋₄ alkyl or COOCH₂CONR⁷ R⁸ or R⁴ is COOC₁₋₄ alkyl or COOCH₂ CONR⁷ R⁸, with a differentalkanol of formula C₁₋₄ alkylOH or a different alcohol of formula HOCH₂CONR⁷ R⁸. The equilibrium of the transesterification reaction may beshifted following art-known methods, e.g. by using an excess of saidalcohol, or by distilling off the liberated alcohol. Transamination canbe accomplished in a similar manner by reaction with an amine HNR⁵ R⁶.

The compounds wherein R^(3-a) or R⁴ is C₁₋₆ alkyl substituted withCOOC₁₋₄ alkyl or COOCH₂ CONR⁷ R⁸ or R⁴ is COOC₁₋₄ alkyl or COOCH₂ CONR⁷R⁸ can be hydrolysed to the corresponding compounds wherein R^(3-a) orR⁴ is C₁₋₆ alkyl substituted with COOH or R⁴ is COOH. Said hydrolysiscan conveniently be conducted by stirring and heating the ester in anaqueous and/or alcoholic medium, e.g. water, methanol, ethanol and thelike, or mixtures thereof, in the presence of a base such as, forexample, sodium hydroxide, potassium hydroxide, potassium carbonate andthe like. In some instances, for example, the 1,1-dimethylethyl ester,said hydrolysis may also be effected by stirring and optionally heatingin an acidic aqueous and/or alcoholic medium as defined hereinabove.

Alternatively the compounds of formula (I-b-1) may be prepared from anintermediate of formula (XI) wherein W³ represents a suitable reactiveleaving group such as, for example, halo, e.g. chloro, or acetate, byreaction with a reagent of formula (XII). ##STR11##

The compounds of formula (I) may also be prepared by cyclizing anintermediate of formula (XIII) or an intermediate of formula (XIV).##STR12##

Following an alternative cyclization procedure, an intermediate offormula (XV) may also be converted into a compound of formula (I).##STR13##

The compounds of formula (I) may also be formed from the quinazolinederivatives (XVI), (XVII) or (XVIII) by cyclization. ##STR14##

In all the above mentioned cyclization reactions, said cyclization maybe carried out by stirring and if desired heating the intermediatestarting material, optionally in a suitable reaction-inert solvent.Appropriate solvents for said cyclization reactions are for example,aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene andthe like; halogenated hydrocarbons, e.g. trichloromethane,tetrachloromethane, chlorobenzene and the like; ethers, e.g.1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,methoxybenzene and the like; dipolar aprotic solvents, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and thelike; or mixtures of such solvents. The water, hydrohalic acid orammonia which is liberated during the cyclization reaction may beremoved from the reaction mixture by azeotropical destillation,destillation, complexation, salt formation and the like methods.

All intermediates of the previous reaction schemes as well as many oftheir precursors are novel and have especially been developed forconversion into the compounds of the present invention. Interesting arethe novel intermediates of formula (II) and (IV), in particular theseintermediates of formula (IV) wherein L is C₁₋₆ alkyloxy, hydroxy oramino, the pharmaceutically acceptable acid and base addition saltsthereof and the stereochemically isomeric forms thereof.

The intermediates of formula (II) can be obtained from the correspondingnitro derivatives of formula (XIX) following art known reductionprocedures. ##STR15##

For example, the nitro derivative of formula (XIX) may be reduced bycatalytic hydrogenation in a suitable solvent, e.g. methanol or ethanol,in the presence of hydrogen and an appropriate catalyst, e.g.platinum-on-charcoal, palladium-on-charcoal, Raney nickel and the like,optionally at an increased temperature and/or pressure. In someinstances it may be useful to add an appropriate catalyst poison such asthiophene to the reaction mixture. Alternatively, said nitro derivativemay also be reduced by a reducing agent such as, for example, sodiumsulfide, sodium hydrogen sulfide, sodium hydrosulfite, titaniumtrichloride, formic acid, N,N-diethylethanamine; iron ammonium chlorideand the like.

The intermediate nitro derivative (XIX) can be prepared from anintermediate of formula (XX) by reaction with an aminoacid (L=OH) or aderivative thereof (L=--O--C₁₋₆ alkyl, --O--phenyl, -amino) of formula(XXI) and more particularly an acid addition salt thereof. ##STR16##

In formula (XX) W² represents an appropriate leaving group as definedhereinabove. The above N-alkylation reaction can conveniently beconducted by stirring, and if desired heating, the reactants in asuitable reaction-inert solvent in the presence of a base.

Suitable solvents are, for example, water; an aromatic solvent, e.g.benzene, methylbenzene, dimethylbenzene, chlorobenzene, methoxybenzeneand the like; a C₁₋₆ alkanol, e.g. methanol, ethanol, 1-butanol and thelike; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; anester, e.g. ethylacetate, γ-butyrolactone and the like; an ether, e.g.1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; a dipolaraprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, pyridine,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylurea,1-methyl-2-pyrrolidinone, nitrobenzene, acetonitrile and the like; or amixture of such solvents. In order to set free the base form of (XXI) incase a salt form is used, and to neutralize the acid which is formedduring the course of the reaction, an appropriate base may be added suchas, for example, an alkali metal or an earth alkaline metal carbonate,hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride oramide, e.g. sodium carbonate, sodium hydrogen carbonate, potassiumcarbonate, sodium hydroxide, calcium oxide, sodium acetate, sodiummethoxide, sodium hydride, sodium amide and the like, or an organic basesuch as, for example, an amine, e.g. N,N-diethylethanamine,N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine,1,4-diazabicyclo[2.2.2]octane, pyridine and the like.

The intermediate of formula (XX) can be obtained from a benzylalcohol offormula (XXII) following art known procedures for converting hydroxygroups into reactive leaving groups. ##STR17## Suitable procedurescomprise, for example, converting the alcohol of formula (XXII) intosulfonyloxy esters by reaction with sulfonyl halides such as, forexample, methanesulfonyl chloride, benzenesulfonyl chloride,4-methylbenzenesulfonyl chloride and the like reagents. Or, the alcoholof formula (XXII) can be converted into the corresponding halide byreaction with a halogenating reagent such as, for example, a hydrohalicacid, e.g. hydrochloric or hydrobromic acid, thionyl chloride, oxalylchloride, phosphoryl chloride or bromide, phosphorous trichloride ortribromide, phosphorus pentachloride, triphenylphosphine withtetrachloromethane or tetrabromomethane and the like halogenatingreagents.

The intermediate benzylalcohol of formula (XXII) can be derived from aprotected alcohol by art-known deprotection procedures. ##STR18## Informula (XXIII) P may represent a suitable protective group such as, forexample, tetrahydropyranyl, 2-methoxyethoxymethyl, 2-methoxypropyl,2-acetoxypropyl, 1-ethoxyethyl and the like; a trialkylsilyl group, e.g.trimethylsilyl, tert.butyldimethylsilyl and the like groups. Saiddeprotection reaction can easily be conducted following art-knownmethods of hydrolyzing acetals and silyl ethers, e.g. by acid hydrolysisin aqueous media. Conversely, the protected intermediates of formula(XXIII) may be obtained from the alkanols of formula (XXII) followingart-known procedures for protecting hydroxy groups. Typically suchprotection reactions may comprise treatment with a vinylether, e.g.dihydropyran, in an inert solvent and in the presence of an acidcatalyst; or O-alkylation or O-silylation with a suitable alkylatingreagent such as, for example, a trialkylsilyl halide, e.g.trimethylsilylchloride, tert.butyldimethylsilylchloride; and the likeprotection reactions. The intermediates of formula (XXIII) wherein X isa radical of formula (b) or (c), said intermediates being represented byformulae (XXIII-b) and (XXIII-c), can easily be prepared from anintermediate of formula (XXIII-a) wherein X is O, following theprocedures described above for the conversion of the compounds offormula (I-a) into the compounds of formula (I-b) and (I-c). ##STR19##The intermediates of formula (XXIII-a) can be prepared from a cyanide offormula (XXIV) following art-known oxidation procedures such asdescribed in J. Org. Chem., 1975, 40, 267. ##STR20##

The cyanides of formula (XXIV) can easily be obtained by an aromaticnucleophilic substitution reaction of a cyanide of formula (XXV) on anitrobenzene of formula (XXVI). ##STR21##

In formula (XXVI) W⁴ represents a reactive leaving group such as, forexample, halo, e.g. chloro or fluoro, nitro, 4-methylbenzenesulfonyloxy,phenyloxy, alkyloxy and the like groups known in the art to be goodleaving groups in aromatic nucleophilic substitution reactions. Saidaromatic nucleophilic substitution reaction can conveniently beconducted by stirring the reactants in the presence of a base in areaction inert solvent such as for example, a dipolar aprotic solvent,e.g. N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethylimidazolidinone, 1,1,3,3-tetramethylurea,1-methyl-2-pyrrolidinone, nitrobenzene and the like solvents; ormixtures thereof. Appropriate bases are sodium hydride, sodium amide,sulfinylbis(methane) sodium salt and the like bases. It may beadvantageous to add to the reaction mixture a crown ether, e.g.1,4,7,10,13,16-hexaoxacyclooctadecane and the like or a complexing agentsuch as for example, tris[2-(2-methoxyethoxy)]ethanamine and the like.Somewhat elevated temperatures may enhance the rate of the reaction.

The intermediates of formula (XXII-a), wherein X is O, can alternativelybe prepared by oxidizing an intermediate of formula (XXVII). ##STR22##

Said oxidation reaction can conveniently be conducted by stirring thereactants in water in the presence of an oxidizing agent such as, forexample, hydrogen peroxide and the like.

The intermediates of formula (XXVII) in turn can be obtained by theaddition of an intermediate of formula (XXV) to2-hydroxymethylnitrobenzene. ##STR23##

Said addition reaction can conveniently be conducted by stirring thereactants in a reaction-inert solvent in the presence of an appropriatebase. Suitable solvents are, for example, dipolar aprotic solvents, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide,pyridine and the like. Appropriate bases are sodium hydroxide, potassiumhydroxide, sodium hydride, sodium amide, sulfinyl bis(methane) sodiumsalt and the like bases.

The intermediates of formula (XXII-a) can also be obtained by thechemoselective reduction of an aldehyde of formula (XXVIII). ##STR24##

Suitable reductants for said selective reduction of the carboxaldehydegroup are, for example, sodium borohydride, sodium cyanoborohydride, andthe like. A particularly interesting mode of conducting said reductioncomprises the addition of a rare-metal salt such as, for example,cerium(III)chloride, to the reaction in order to increase theselectivity.

The aldehydes of formula (XXVIII) in turn can be obtained by hydrolyzingin an acidic aqueous medium an α-aminocyanide of formula (XXIX), whereinboth R¹⁰ radicals represent an alkyl group such as methyl, ethyl and thelike, or both R¹⁰ taken together form an alkanediyl radical such as,1,2-ethanediyl, 1,3-propanediyl, 2,2-dimethyl-1,3-propanediyl and thelike.

In formula (XXIX) and hereinafter the group -NR'R' represents adialkylamino group or a heterocyclic radical such as, for example,morpholino, piperidino, pyrrolidino and the like groups. ##STR25##

The intermediates of formula (XXIX) in turn can be prepared by anaromatic nucleophilic substitution reaction on a nitrobenzene of formula(XXXI) as described hereinabove for the preparation of the intermediatesof formula (XXIV). ##STR26##

The reagent of formula (XXX) can easily be prepared from an appropriatealdehyde by reaction with sodium cyanide, potassium cyanide and the likecyanides, in the presence of an amine HNR'R' and sodium hydrogensulfite. Suitable solvents are for example, water, alkanols, e.g.methanol, ethanol and the like, and mixtures thereof.

In a number of instances, the intermediates of formula (XIX) and (II)wherein X is O, said intermediates being represented by formula (XIX-a)and (II-a), can be derived directly from an intermediate of formula(XXVIII) by reductive N-alkylation with an amino acid derivative offormula (XXI) or a salt thereof. ##STR27##

Said reductive N-alkylation reaction can conveniently be conductedfollowing art-known procedures, i.e. by stirring and optionally heatinga mixture of the ingredients in a reaction-inert solvent in the presenceof a suitable reductant and an equivalent of a base to set free theamino acid from its salt. Suitable bases are alkali metal carboxylates,e.g. sodium acetate, potassium acetate, potassium propionate and thelike. For example, said mixture may be catalytically reduced in thepresence of hydrogen and a hydrogenation catalyst such aspalladium-on-charcoal, platinum-on-charcoal and the like, thus yieldingan intermediate of formula (II-a). Alternatively, hydrides, e.g. sodiumborohydride, sodium cyanoborohydride and the like; formic acid or a saltthereof, particularly the ammonium salt, may be employed to effect thedesired reductive N-alkylation to an intermediate of formula (XIX-a).

The thus obtained intermediates of formula (XIX-a) can further beconverted into the corresponding free oxime derivatives wherein X isNOH, said intermediates being represented by formula (XIX-b), byreaction with hydroxylamine or a salt thereof in a lower alkanol suchas, for example, methanol, ethanol, 1-propanol, 2-propanol and the likeand a suitable base such as, for example, potassium fluoride, potassiumacetate and the like. ##STR28##

The intermediates of formula (XIX-b) are particularly useful forO-alkylating or O-silylating the oxime group with a reagent of formulaR^(3-a) -W² as described hereinbefore for the preparation of compoundsof formula (I-b-1) from the compounds of formula (I-b-2). Theintermediates of formula (XIX-b) may occur in their E- or Z-form or asmixtures thereof. Mixtures of said E- and Z-forms can be isomerizedmainly to the E-form by stirring in a suitable solvent in the presenceof an acid such as, for example, hydrochloric acid. Suitable solventsare, for example, alcohols, e.g. propanol, isopropanol and the like;ethers, e.g. 1,4-dioxane, tetrahydrofuran and the like or mixtures ofsuch solvents.

The intermediates of formula (XXII) wherein X is NOH, said intermediatesbeing represented by formula (XXII-b) can also be prepared by reducingan ester of formula (XXXII) wherein R¹¹ represents alkyl. ##STR29##

Said reduction can conveniently be conducted by treating the ester in areaction-inert solvent such as an ether, e.g. tetrahydrofuran,1,1'-oxybisethane and the like, with a reducing agent such as sodiumborohydride.

The intermediates of formula (XXXII) are obtained from the correspondingketones or aldehydes (XXXIII) following procedures as describedhereinabove for the preparation of the compounds of formula (I-b) fromthose of formula (I-a).

The ketones may be prepared by reacting an organometallic compound R¹²-M, wherein R¹² represents R but is other than hydrogen, and M is ametal group such as lithium, magnesium halide, copper lithium, with thealdehyde (XXXIII) and oxidizing the thus obtained alcohol to the ketone.##STR30##

The aldehyde (XXXIII) is prepared following art-known procedures fromthe corresponding methyl group by oxidation to the carboxylic acid,reduction to the alcohol and oxidation to the aldehyde.

The intermediates of formula (V) wherein X is O, said intermediatesbeing represented by formula (V-a) can be prepared by N-alkylating anintermediate (XXXIV) with an appropriate acetate derivative (XXXV)wherein W and L are reactive leaving groups as defined hereinbefore.##STR31##

The intermediate (XXXIV) in turn can be obtained from (XXXVI) byS-alkylation with an alkylhalide R⁹ -W, e.g. methyliodide, followingart-known procedures.

The intermediate (XXXVI) finally is prepared by the Friedel-Craftsacylation of 3,4-dihydro-2(1H)-quinazolinethione with a suitable acidhalide (XXXVII) in the presence of an appropriate Lewis acid such as,for example, aluminum chloride, ferric chloride and the like, in asolvent, preferably a dipolar aprotic solvent, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethylimidazolidinone, 1,1,3,3,-tetramethylurea and the like.##STR32##

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereochemically isomeric forms thereof, are potentinhibitors of the phosphodiesterase type III_(c) (cardiotonic-sensitivePDE III) (also designated family III_(A1) in the novel classification byJ. A. Beavo and D. H. Reifsnyder, TIPS Reviews, April 1990, pp. 150-155)of warm-blooded animals, in particular humans. Inhibition of PDE III_(c)leads to an elevation of cAMP in cardiac muscle, which in turn enhancessarcolemmal entry of Ca²⁺ into the cell, increases the release andreuptake of Ca²⁺ by the sarcoplasmic reticulum and probably alsoincreases the sensitivity of contractile proteins to Ca²⁺. As a resultan increased contractile force of the heart ensures (positive inotropy)as well as a faster relaxation of the heart (positive lusitropy).

Particularly important is the observation that the positive inotropicand lusitropic effects generally do not coincide with a simultaneousincrease of other haemodynamic variables such as heart rate and bloodpressure. Concommittant increases of heart rate and/or blood pressurewould indeed put extra strain on the heart and cancel the beneficialpositive cardiac inotropy and lusitropy. In vivo experiments with theinstant compounds of formula (I) show moderate systemic vasodilation andhence a decrease in blood pressure. The heart rate generally onlyincreases at high doses. In all, the instant compounds of formula (I)dramatically increase cardiac output by cardiac positive inotropy andlusitropy and without major influence on heart rate and/or bloodpressure. The novel intermediates of formula (IV) also are inhibitors ofthe phosphodiesterase type III_(c).

Consequently, the subject compounds are considered to be valuabletherapeutical drugs for treating warm-blooded animals, particularlyhumans, suffering from Congestive Heart Failure. Congestive HeartFailure is a pathophysiological state that is defined by the inabilityof the heart to pump adequate amounts of blood to the peripheral sitesof the organism, with consequent failure to meet the metabolicrequirement of the body. Said condition may result from a heart attack,infection of the heart, chronic hypertension, deficiencies in theoperation of the heart valves and other disorders of the heart leadingto Congestive Heart Failure.

In view of their useful positive inotropic and lusitropic properties,the subject compounds may be formulated into various pharmaceuticalforms for administration purposes. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcompound, in base or acid addition salt form, as the active ingredientis combined in intimate admixture with a pharmaceutically acceptablecarrier, which may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions: or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wettable agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. Addition salts of the subject compounds are obviouslymore suitable in the preparation of aqueous compositions due to theirincreased water solubility.

Especially noteworthy as complexants and/or solubilizers are β-CD,2,6-dimethyl-β-CD and in particular 2-hydroxypropyl-β-CD,2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD and 2-hydroxypropyl-γ-CD. Inthe aforementioned cyclodextrin derivatives, the DS (degree ofsubstitution, i.e. the average number of substituted hydroxy functionsper glucose unit) preferably is in the range of 0.125 to 3, inparticular 0.3 to 2, more in particular 0.3 to 1 and the MS (molardegree of substitution, i.e. the average number of moles of thesubstituting agent per glucose unit) is in the range of 0.125 to 10, inparticular of 0.3 to 3 and more in particular 0.3 to 1.5, preferably of0.35 to 0.50. Said compositions may conveniently be prepared bydissolving the cyclodextrin or ether derivative thereof in water andadding thereto a subject compound as well as other adjuvants andcomponents such as, for example, sodium chloride, potassium nitrate,glucose, mannitol, sorbitol, xylitol and buffers such as, for example,phosphate, acetate or citrate buffers; and optionally concentrating ordrying the solution by evaporation under reduced pressure or bylyophilization. The amount of the cyclodextrin or ether derivativethereof in the final composition generally ranges from about 1% to about40% by weight, particularly form 2.5% to 25% and more particularly from5% to 20%.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions and the like, and segregatedmultiples thereof.

In view of the usefulness of the subject compounds in the treatment ofCongestive Heart Failure it is evident that the present inventionprovides a method of treating warm-blooded animals suffering fromCongestive Heart Failure, said method comprising the systemicadministration of a pharmaceutically effective amount of a compound offormula (I), an intermediate of formula (IV) or a pharmaceuticallyacceptable addition salt thereof in admixture with a pharmaceuticalcarrier. Those of skill in the treatment of Congestive Heart Failurecould easily determine the effective daily amount from the test resultspresented here. In general it is contemplated that an effective dailyamount would be from 0.01 mg/kg to 4 mg/kg body weight, more preferablyfrom 0.04 mg/kg to 2 mg/kg body weight.

It is evident that said effective daily amount may be lowered orincreased depending on the response of the treated subject and/ordepending on the evaluation of the physician prescribing the compoundsof the instant invention. The effective daily amount ranges mentionedhereinabove are therefore guidelines only and are not intended to limitthe scope or use of the invention to any extent.

The following examples are intended to illustrate and not to limit thescope of the present invention. Unless otherwise stated all partstherein are by weight.

EXPERIMENTAL PART A. Preparation of Intermediates EXAMPLE 1

a) A mixture of 25 parts of 5-chloro-2-nitrobenzenemethanol, 13.3 partsof dihydro-2H-pyran, 300 parts of dichloromethane and 0.28 parts of4-methylbenzenesulfonic acid was stirred for 2 hours at refluxtemperature. After cooling, the reaction mixture was neutralized withsodium carbonate and stirred for 10 min. The whole was filtered and thefiltrate was evaporated. The residue was co-evaporated withmethylbenzene and then purified by column chromatography (silica gel;CHCl₃). The eluent of the desired fraction was evaporated and theresidue was co-evaporated with methylbenzene, yielding 36 parts (99.6%)of 2-[(5-chloro-2-nitrophenyl)methoxy]tetrahydro-2H-pyran (interm. 1).

b) To a suspension of 7.13 parts of a sodium hydride dispersion 50% inmineral oil in 94 parts of N,N-dimethylacetamide there was addeddropwise a solution of 9.1 parts of benzeneacetonitrile in 18.8 parts ofN,N-dimethylacetamide. After hydrogen evolution had ceased, there wereadded 1.28 parts ofN,N-di[2(2-methoxyethoxy)ethyl]-2-(2-methoxyethoxy)ethanamine and asolution of 20.2 parts of intermediate (1) in 28.2 parts ofN,N-dimethylacetamide. After 15 min, the reaction mixture was pouredinto ice-water and the whole was neutralized. The product was extractedwith dichloromethane and the extract was dried, filtered and evaporated,yielding 26.2 parts (100%) of4-nitro-α-phenyl-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzeneacetonitrile(interm. 2).

c) A mixture of 26.2 parts of intermediate (2), 10.2 parts of potassiumcarbonate and 376 parts of N,N-dimethylacetamide was aerated at roomtemperature, while stirring. The reaction mixture was poured into waterand the product was extracted with 2,2'-oxybispropane. The extract wasdried, filtered and evaporated, yielding 25 parts (98.6%) of[4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]phenyl-methanone (interm. 3).

d) A mixture of 50 parts of intermediate (3), 1.9 parts of4-methylbenzenesulfonic acid and 400 parts of methanol was stirred atroom temperature. The reaction mixture was neutralized with sodiumcarbonate, stirred at room temperature for 15 min and filtered. Thefiltrate was evaporated and the residue was stirred in a mixture ofwater and 2,2'-oxybispropane for 15 min. The whole was washed with NaCl(sat.), dried, filtered and evaporated. The residue was co-evaporatedwith methylbenzene and was then purified by column chromatography(silica gel; CHCl₃ /CH₃ OH 98:2). The eluent of the desired fractionswas evaporated and the residue was crystallized from a mixture ofmethylbenzene and hexane. The product was filtered off, washed with amixture of hexane and methylbenzene and with hexane, and dried in vacuoat 40°-50° C., yielding 9.7 parts (25.9%) of[3-(hydroxymethyl)-4-nitrophenyl] phenylmethanone; mp. 71.3° C. (interm.4).

e) to a stirred and cooled (0° C.) mixture of 27.5 parts of intermediate(4), 11.9 parts of N,N-diethylethanamine and 650 parts ofdichloromethane there were added dropwise 13.3 parts of methanesulfonylchloride. The reaction mixture was partitioned between dichloromethaneand water. The organic layer was separated, dried, filtered andevaporated, yielding 36 parts (100%) of 5-benzoyl-2-nitrobenzenemethanolmethanesulfonate (ester).

To a stirred amount of 385 parts of dimethyl sulfoxide were added 22.3parts of ethyl glycine monohydrochloride. When a clear solution wasobtained, there were added 13.4 parts of sodium hydrogen carbonate and,after stirring for 15 min, 70 parts of molecular sieve 4Å. Stirring wascontinued for 15 min. Next there were added dropwise a solution of 34.3parts of 5-benzoyl-2-nitrobenzenemethanol methanesulfonate (ester) in 77parts of dimethyl sulfoxide. This reaction mixture was used as such forthe preparation of intermediate (6). Theoretical yield: 28 parts (100%)of [3-(chloromethyl)-4-nitrophenyl] phenylmethanone (interm. 5).

f) To the reaction mixture, obtained in the preparation of intermediate(5), there were added 9 parts of sodium hydrogen carbonate. The wholewas stirred overnight at 50° C. and was then poured into 1000 parts ofwater. The precipitate was filtered off and stirred in 2-propanone for15 min. This solution was filtered and the filtrate was evaporated. Theresidue was taken up in methylbenzene and the whole was washed withwater, dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CHCl₃ /C₂ H₅ OH 98:2). The eluent ofthe desired fractions was evaporated, yielding 23.7 parts (68.2%) ofethyl N-[(5-benzoyl-2-nitrophenyl)methyl]glycine (interm. 6).

g) A mixture of 3.7 parts of intermediate (6), 2 parts of a solution ofthiophene in methanol and 119 parts of ethanol was hydrogenated atnormal pressure and at room temperature with 2 parts ofplatinum-on-charcoal catalyst 5%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was co-evaporated with methylbenzene,yielding 3.19 parts (95%) of ethylN-[(2-amino-5-benzoylphenyl)methyl]glycine (interm. 7).

EXAMPLE 2

a) To a stirred solution of 21.2 parts of intermediate (5) in 158 partsof acetonitrile, there were added successively 17.9 parts of ethylβ-alanine monohydrochloride and 20.4 parts of N,N-diethylethanamine.Stirring was continued overnight at 50° C. The reaction mixture wasfiltered and the filtrate was evaporated. The residue was partitionedbetween NaCl (sat.) and dichloromethane. The organic layer wasseparated, dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CHCl₃ /C₂ H₅ OH 99:1). The eluent ofthe desired fraction was evaporated and the residue was co-evaporatedwith methylbenzene, yielding 15.3 parts (55.8%) of ethylN-[(5-benzoyl-2-nitrophenyl)methyl]-β-alanine (interm. 8).

b) A mixture of 15.3 parts of intermediate (8), 2 parts of a solution ofthiophene in methanol 4% and 198 parts of ethanol was hydrogenated atnormal pressure and room temperature with 5 parts ofpalladium-on-charcoal catalyst 5%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was co-evaporated with methylbenzene,yielding 12.8 parts (93.4%) of ethylN-[(2-amino-5-benzoylphenyl)methyl]-β-alanine (interm. 9).

In a similar manner there were also prepared: methylN-[(2-amino-5-benzoylphenyl)methyl]-2-methylalanine (interm. 10) andethyl 1-[[(2-amino-5-benzoylphenyl)methyl]amino]cyclopropanecarboxylate(interm. 11).

EXAMPLE 3

a) A mixture of 20 parts of intermediate (3), 4.45 parts ofhydroxylamine monohydrochloride and 98 parts of pyridine was stirred fora few hours at reflux temperature. The solvent was evaporated and theresidue was purified by column chromatography (silica gel; CHCl₃ /CH₃ OH98:2). The eluent of the first and second fraction was evaporated andthe residues were separately co-evaporated with ethanol (3×) and withmethylbenzene (1×). From the second fraction there were obtained 4.8parts (30.2%) of product. The first fraction was chromatographed again(silica gel; CHCl₃ /CH₃ OH 98:2) and evaporation of the eluent yieldedan additional 9 parts (56.4%) of product. Total yield: 13.8 parts(86.6%) of (E+Z)-[3-(hydroxymethyl)-4-nitrophenyl] phenylmethanone,oxime (interm. 12).

b) To a stirred solution of 11.3 parts of intermediate (12) in 245 partsof N,N-dimethylformamide there were added portionwise 1.99 parts of asodium hydride dispersion 50% in mineral oil. Stirring at roomtemperature was continued for 1/2 hour and then there were added at once6.9 parts of ethyl 2-bromoacetate. After stirring overnight at roomtemperature, the reaction mixture was poured into NaCl (sat.). Theproduct was extracted with 2,2'-oxybispropane and the extract was washedwith water, dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CHCl₃). The eluent of the desiredfraction was evaporated and the residue was co-evaporated withmethylbenzene, yielding 8.9 parts (59.8%) of ethyl(E+Z)-2-[[[[3-(hydroxymethyl)-4-nitrophenyl]phenylmethylene]amino]oxy]acetate(interm. 13).

c) To a stirred and cooled (0° C.) mixture of 8.9 parts of intermediate(13), 2.6 parts of N,N-diethylethanamine and 260 parts ofdichloromethane there were added dropwise 2.84 parts of methanesulfonylchloride. Stirring was continued at 0° C. and the mixture was allowed toreach room temperature overnight. The product was extracted with 130parts of dichloromethane and the extract was washed with water (2×),dried, filtered and evaporated. The residue was co-evaporated withmethylbenzene, yielding 9.3 parts (100%) of a mixture of ethyl(E+Z)-2-[[[[3-(chloro-methyl)-4-nitrophenyl]phenylmethylene]amino]oxy]acetate(interm. 14) and ethyl(E+Z)-2-[[[[3-[(methylsulfonyloxy)methyl]-4-nitrophenyl]phenylmethylene]amino]oxy]acetate(interm. 15) (15:85).

d) A mixture of 9.3 parts of intermediate (14) and intermediate (15) in132 parts of dimethyl sulfoxide, 5.15 parts of ethyl glycinemonohydrochloride and 7.7 parts of N,N-diethylethanamine was stirred at50°-60° C. The reaction mixture was poured into NaCl (sat.) and theproduct was extracted with 2,2'-oxybispropane. The extract was washedwith water (2×), dried, filtered and evaporated. The residue wasco-evaporated with methylbenzene (2×), yielding 6.6 parts (60%) of ethyl(E+Z)-[[5-[[(2-ethoxy-2-oxoethoxy)imino]phenylmethyl]-2-nitrophenyl]methyl]glycine(interm. 16).

e) A mixture of 6.6 parts of intermediate (16), 4 parts of a solution ofthiophene in methanol and 200 parts of ethanol was hydrogenated atnormal pressure and at room temperature with 2 parts ofplatinum-on-charcoal catalyst 5%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was co-evaporated with methylbenzene,yielding 5.9 parts (96.4%) of ethyl(E+Z)-N-[[2-amino-5-[[(2-ethoxy-2-oxoethoxy)imino]phenylmethyl]phenyl]methyl]glycine(interm. 17).

In a similar manner there were also prepared:

ethyl(E)-N-[[2-amino-5-[[[[6-(cyclohexylmethylamino)-6-oxohexyl]oxy]imino]-phenylmethyl]phenyl]methyl]glycine(interm. 18) and

ethyl(E+Z)-5-[[[[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]phenylmethylene]amino]oxy]pentanoate(interm. 19).

EXAMPLE 4

To a suspension of 39.3 parts of intermediate (12) in 395 parts of2-methyl-2-propanol there were added 23 ml of a solution of potassiumhydroxide in ethanol and 23.1 parts of ethyl 2-propenoate. The whole wasstirred for 3 days at 40° C. The reaction mixture was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CHOH 98:2). The eluent of thedesired fraction was evaporated, yielding 29.9 parts (57.4%) of ethyl(E+Z)-3-[[[[3-(hydroxymethyl)-4-nitrophenyl]phenylmethylene]amino]oxy]propanoate(interm. 20). Following the reaction procedure described in Example3(c), (d) and (e), intermediate (20) was converted into ethyl(E+Z)-3-[[[[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]phenylmethylene]amino]oxy]propanoate(interm. 21).

EXAMPLE 5

a) To a stirred mixture of 20 parts of intermediate (3) in 98 parts ofpyridine, there were added 4.45 parts of hydroxylaminemonohydrochloride. The whole was refluxed for a few hours and was thenevaporated. The residue was purified by column chromatography (silicagel; CHCl₃ /CH₃ OH 98:2). The eluent of the desired fraction wasevaporated and the residue was co-evaporated with ethanol (3×) andmethylbenzene (1×). The product was chromatographed again (silica gel;CHCl₃ /CH₃ OH 100:0→98:2). Evaporation of the eluent yielded 6.4 parts(30.7%)(E+Z)-[4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]phenylmethanone,oxime (interm. 22).

b) To a stirred mixture of 6.4 parts of intermediate (22) in 44 parts ofdimethyl sulfoxide, there were added 3.29 parts of potassium carbonateand 4.53 parts of 2-chloro-N-cyclohexyl-N-methylacetamide. Stirring wascontinued overnight at room temperature. The reaction mixture was pouredinto NaCl (sat.) and the product was extracted with dichloromethane. Theextract was dried, filtered and evaporated, yielding 10 parts (100%) of(E+Z)-N-cyclohexyl-N-methyl-2-[[[[4-nitrol-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]phenylmethylene]amino]oxy]acetamide(interm. 23).

c) A solution of 12.55 parts of intermediate (23) in 200 parts ofmethanol was treated with 0.45 parts of 4-methylbenzenesulfonic acid andstirred at room temperature. The reaction mixture was neutralized withsodium carbonate and stirred for 10 min. The whole was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography (silica gel; CHCl₃ /CH₃ OH 98:2). The eluent of thedesired fractions was evaporated and the residue was co-evaporated withethanol (2×) and with methylbenzene (2×), yielding 8.6 parts (82.2%) of(E+Z)-N-cyclohexyl-2-[[[[3-(hydroxymethyl)-4-nitro-phenyl]phenylmethylene]amino]oxy]-N-methylacetamide(interm. 24). Following the reaction procedure described in Example 3(c), (d) and (e), intermediate (24) was converted into ethyl(E+Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]phenylmethyl]phenyl]methyl]glycine(interm. 25). In a similar manner there was also prepared ethyl(E+Z)-4-[[[[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]phenylmethylene]amino]oxy]butanoate(interm. 26).

EXAMPLE 6

a) To a cooled (10° C.) mixture of 12.96 parts of a dispersion of sodiumhydride in mineral oil (50%) in 801 parts of tetrahydrofuran there wereadded 60.5 parts of ethyl (diethoxyphosphinyl)acetate under a nitrogenatmosphere. After stirring for 20 min at 10°-15° C., there was added asolution of 42 parts of intermediate (3) in 45 parts of tetrahydrofuranunder nitrogen. Stirring was continued overnight at 60° C. The reactionmixture was poured into ice-water and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated and theresidue was co-evaporated with methylbenzene, yielding 55 parts (100%)of ethyl(E+Z)-3-[4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]-3-phenyl-2-propenoate(interm. 27).

b) A mixture of 50.6 parts of intermediate (27), 2.3 parts of4-methylbenzenesulfonic acid and 395 parts of methanol was stirred for20 hours at room temperature. The reaction mixture was neutralized withsodium carbonate and stirred for 5 min. The whole was filtered and thefiltrate was evaporated. The residue was dissolved in dichloromethaneand this solution was washed with water, dried, filtered and evaporated.The residue was purified by column chromatography (silica gel; CH₂ Cl₂).The eluent of the desired fraction was evaporated, yielding 28 parts(69.5%) of ethyl(E+Z)-3-[3-(hydroxymethyl)-4-nitrophenyl]-3-phenyl-2-propenoate (interm.28).

c) To a cooled (0°-5° C.) solution of 28 parts of intermediate (28) and9.7 parts of N,N-diethylethanamine in 665 parts of dichloromethane therewere added dropwise 10.4 parts of methanesulfonyl chloride. Afterstirring for 1/2 hour at 0°-5° C., the reaction mixture was washed withwater, dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CH₂ Cl₂). The eluent of the desiredfraction was evaporated and the residue was co-evaporated withmethylbenzene, yielding 27 parts (77.4%) of ethyl(E+Z)-3-[3-[[(methylsulfonyl)oxy]methyl]-4-nitrophenyl]-3-phenyl-2-propenoate(interm. 29).

d) To a solution of 27 parts of intermediate (29) in 237 parts ofacetonitrile, there were added successively 14 parts of ethyl glycinemonohydrochloride and 17 parts of N,N-diethylethanamine. The whole wasstirred overnight at 50° C. and then evaporated. The residue was takenup in dichloromethane. This solution was washed with water, dried,filtered and evaporated, yielding 26 parts (94.1%) of ethyl(E+Z)-3-[3-[[(2-ethoxy-2-oxoethyl)amino]methyl]-4-nitrophenyl]-3-phenyl-2-propenoate(interm. 30).

e) A mixture of 26 parts of intermediate (30), 18 parts of iron powder,17.4 parts of ammonium chloride, 596 parts of trichloromethane and 200parts of water was refluxed for 2 days. The reaction mixture wasfiltered over diatomaceous earth. The trichloromethane layer of thefiltrate was separated, dried, filtered and evaporated. The residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 99:1).The eluent of the desired fraction was evaporated and the residue wasco-evaporated with methylbenzene, yielding 18 parts (72.4%) of ethyl(E+Z)-3-[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]-3-phenyl-2-propenoate(interm. 31).

f) A mixture of 13.2 parts of intermediate (30) and 119 parts of ethanolwas hydrogenated at normal pressure and room temperature with 2 parts ofplatinum-on-charcoal catalyst 5%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was purified by column chromatography(silica gel; CHCl₃ /C₂ H₅ OH 98:2). The eluent of the (E)-isomerfraction was evaporated, yielding 4.3 parts (35.1%) of ethyl(E)-3-[4-amino-3-[[(2-ethoxy-2-oxoethyl)-amino]methyl]phenyl]-3-phenyl-2-propenoate(interm. 32).

g) To a cooled (0°-5° C.) solution of 39.1 parts of intermediate (28),18.2 parts of N,N-diethylethanamine and 333 parts of dichloromethanethere was added dropwise a solution of 16.5 parts of methanesulfonylchloride in 40 parts of dichloromethane. After stirring for 15 min at0°-5° C., the reaction mixture was poured into ice-water. The organiclayer was separated, dried, filtered and evaporated. The residue wasstirred with activated charcoal in 1,1'-oxybisethane. This solution wasfiltered and concentrated. The crystallized product was filtered off andpurified by column chromatography (silica gel; CHCl₃ /C₂ H₅ OH 98:2).The eluent of the desired fraction was evaporated and the residue wascrystallized from 1,1'-oxybisethane (2×). The product was filtered offand dried, yielding 16.8 parts (34.5%) of ethyl(Z)-3-[3-[[(methylsulfonyl)oxy]methyl]-4-nitrophenyl]-3-phenyl-2-propenoate;mp. 87.8° C. (interm. 33). Following the reaction procedures describedin steps (d) and (f) hereinbefore, intermediate (33) was converted intoethyl(Z)-3-[4-amino-3-[[(2-ethoxy-2-oxoethyl)-amino]methyl]phenyl]-3-phenyl-2-propenoate(interm. 34).

EXAMPLE 7

a) To a stirred amount of 1076 parts of N,N-dimethylacetamide there wereadded successively 63.24 parts of a dispersion of sodium hydride inmineral oil (50%) and a solution of 92.46 parts of4-fluorobenzeneacetonitrile in 47 parts of N,N-dimethylacetamide. Afterhydrogen evolution had ceased, there were added dropwise 9.85 parts ofN,N-di[2-(2-methoxyethoxy)ethyl]-2-(2-methoxyethoxy)ethanamine and asolution of 179.19 parts of intermediate (1) in 94 parts ofN,N-dimethylacetamide. The mixture was stirred for 15 min. and thenpartitioned between ice-water and dichloromethane. After neutralizationwith formic acid, the product was extracted with dichloromethane. Theextract was dried, filtered and concentrated, yielding theoretically244.5 parts (100%) ofα-(4-fluorophenyl)-4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzeneacetonitrilein solution (interm. 35).

b) A mixture of 244.2 parts of intermediate (35), 100.9 parts of sodiumcarbonate and 1316 parts of N,N-dimethylacetamide was aerated at roomtemperature for 48 hours, while stirring. The reaction mixture waspoured into 3000 parts of water and the whole was extracted with2,2'-oxybispropane. The formed solid was filtered off, recrystallizedfrom 2-propanol and dried in vacuo, yielding a first fraction of 58.5parts (24.7%) of product. The organic layer of the filtrate wasseparated, dried, filtered and evaporated. The residue was stirred inhexane, filtered off and dried, yielding an additional 157 parts (66.2%)of product. Total yield: 215.5 parts (90.9%) of (4-fluorophenyl)[4-nitro-3-[[(tetrahydro-2H-2-pyranyl)oxy]methyl]phenyl]methanone; mp.105.4° C. (interm. 36). Following the reaction procedures described inExample 1 (d), (e); Example 3 (d) and Example 2 (b), intermediate (36)was converted into ethylN-[[2-amino-5-(4-fluorobenzoyl)phenyl]methyl]glycine (interm. 37).

Similarly, following the reaction procedures described in Example 1 (d);Example 5 (a), (b); Example 1 (e); Example 2 (a) and Example 1 (g),intermediate (36) was also converted into ethyl(E)-N-[[2-amino-5-[[[2-[(cyclohexyl)methylamino]-2-oxoethoxy]imino](4-fluorophenyl)methyl]phenyl]methyl]glycine(interm. 38). Following the reaction procedures described in Example 1(d), (e); Example 2(a) and (b), intermediate (36) was converted intoethyl(E+Z)-N-[[2-amino-5-[[[2-[(cyclohexyl)methylamino]-2-oxoethoxy]imino](4-fluorophenyl)methyl]phenyl]methyl]glycine(interm. 39).

EXAMPLE 8

a) To a stirred and cooled (<15° C.) mixture of 134 parts of potassiumhydroxide and 940 parts of pyridine were added portionwise 92 parts of2-nitrobenzenemethanol. Next there were added 132.5 parts of4-methoxybenzeneacetonitrile and stirring was continued for 4 hours atroom temperature. The reaction mixture was diluted with 3000 parts ofice-water and the whole was acidified with 1270 parts of hydrochloricacid. The precipitate was filtered off, stirred overnight inmethylbenzene and dried in vacuo at 60° C., yielding 128.8 parts (50.7%)ofα-[4-hydroxyimino)-3-(hydroxymethyl)-2,5-cyclohexadien-1-ylidene]-4-methoxybenzeneacetonitrile(interm. 40).

b) To a stirred solution of 340 parts of potassium hydroxide in 1700parts of water there were added 66.4 parts of intermediate (40). Next asolution of 394 parts of hydrogen peroxide in 500 parts of water wasadded dropwise. Stirring was continued for 3 hours and then the productwas extracted with a mixture of trichloromethane and methanol (90:10).The extract was dried, filtered and evaporated. The residue was purifiedby column chromatography (silica gel; CHCl₃). The eluent of the desiredfractions was collected and the residue was stirred in2,2'-oxybispropane. The product was filtered off and dried, yielding21.7 parts (32.8%) of[3-(hydroxymethyl)-4-nitrophenyl](4-methoxyphenyl)-methanone; mp. 116.5°C. (interm. 41).

Following the reaction procedure described in Example 3 (c), (d) and(e), intermediate (41) was converted into ethylN-[[2-amino-5-(4-methoxybenzoyl)phenyl]methyl]glycine (interm. 42).

EXAMPLE 9

a) A mixture of 14.7 parts of 5-chloro-2-nitrobenzaldehyde, 13.3 partsof trimethoxymethane, 0.15 parts of 4-methylbenzenesulfonic acid and 64parts of methanol was stirred at reflux temperature. After cooling, thereaction mixture was neutralized with sodium carbonate and stirred for 5min. The whole was filtered and the filtrate was evaporated, yielding18.3 parts (99.7%) of 4-chloro-2-(dimethoxymethyl)-1-nitrobenzene(interm. 43).

b) A solution of 78.1 parts of sodium hydrogen sulfite in 400 parts ofwater was stirred for 15 min at 20° C. under a nitrogen atmosphere.After cooling to -5° C., there were added portionwise 100 parts of4-bromobenzaldehyde and stirring was continued for 20 min at 10° C. Nextthere were added portionwise 65.3 parts of morpholine and, afterstirring for 15 min, a solution of 26.9 parts of sodium cyanide in 90parts of water. The mixture was stirred for 22 hours at 50° C. and wasthen treated with 8.7 parts of a sodium hydroxide solution 50%. Theproduct was filtered off, washed with water and dried in vacuo at 50°C., yielding 138.5 parts (98.5%) ofα-(4-bromophenyl)-4-morpholineacetonitrile (interm. 44).

c) To a stirred solution of 21.1 parts of a sodium hydride dispersion50% in mineral oil in 940 parts of N,N-dimethylformamide there was addeddropwise a solution of 112.5 parts of intermediate (44) in 207 parts ofN,N-dimethylformamide under a nitrogen atmosphere. After stirring for 2hours and subsequent cooling to 0°-5° C., there was added dropwise asolution of 94.9 parts of intermediate (43) in 263 parts ofN,N-dimethylformamide. Stirring was continued for 45 min at roomtemperature. The reaction mixture was poured into ice-water. Theprecipitate was filtered off and dissolved in 2,2'-oxybispropane. Thissolution was washed with water, dried and filtered. The filtrate wasleft to crystallize, yielding two crops of respectively 60.2 parts and36.3 parts of product. Addition of dichloromethane to the mother liquoryielded a third crop of 77.7 parts of product. Total yield: 174.2 parts(91.4%) ofα-(4-bromophenyl)-α-[3-(dimethoxymethyl)-4-nitrophenyl]-4-morpholineacetonitrile;mp. 142.8° C. (interm. 45).

d) To a stirred mixture of 390 parts of 2-propanol, saturated withhydrochloric acid and 350 parts of water there was added dropwise asolution of 172.4 parts of intermediate (45) in 361 parts of1,4-dioxane. After refluxing for 3 hours and stirring at roomtemperature overnight, the precipitate was filtered off (*) and taken upin a mixture of methanol and dichloromethane. The whole was basifiedwith NH₄ OH (aq.), washed with water, dried, filtered and evaporated,yielding a first fraction of 83 parts (62.2%) of product. The filtrate(*) was evaporated. The residue was taken up in water and the whole wasextracted with dichloromethane. The extract was washed with water,dried, filtered, evaporated. The residue was co-evaporated withmethylbenzene and stirred in 2,2'-oxybispropane. The product wasfiltered off and dried in vacuo at 40° C., yielding an additional 4.5parts (3.4%) of product. Total yield: 87.5 parts (65.6%) of5-(4-bromobenzoyl)-2-nitro-benzaldehyde; mp. 150.9° C. (interm. 46).

e) To a stirred and cooled (ice-bath) solution of 83 parts ofintermediate (46), 11.2 parts of cerium(III)chloride heptahydrate and1540 parts of dimethyl sulfoxide there were added portionwise 2.5 partsof sodium tetrahydroborate. After stirring for 10 min, there was addedan ammonium chloride solution. The product was successively extractedwith 2,2'-oxybispropane (3×) and with dichloromethane (2×). The combinedextracts were washed with water, dried, filtered and evaporated. Theresidue was purified twice by column chromatography (silica gel; CH₂ Cl₂/CH₃ OH 99.5:0.5). The eluent of the desired fraction was evaporated,yielding 56.4 parts (67.1%) of(4-bromophenyl)[3-(hydroxymethyl)-4-nitrophenyl]methanone (interm. 47).Following the reaction procedure described in Example 3 (c), (d) and(e), intermediate (47) was converted into ethylN-[[2-amino-5-(4-bromobenzoyl)phenyl]methyl]glycine (interm. 48).

In a similar manner there were also prepared:

ethyl N-[[2-amino-5-(3-methoxybenzoyl)phenyl]methyl]glycine (interm.49),

ethyl N-[[2-amino-5-(4-methylbenzoyl)phenyl]methyl]glycine (interm. 50),

ethyl N-[[2-amino-5-(3,4-dimethoxybenzoyl)phenyl]methyl]glycine (interm.51),

ethyl [[2-amino-5-(4-chlorobenzoyl)phenyl]methyl]glycine (interm. 52).

Following the reaction procedures described in Examples 5 (a), (b);Example 3 (c), (d) and (e), intermediate (47) was also converted intoethyl(E+Z)-N-[[2-amino-5-[(4-bromophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]methyl]phenyl]methyl]glycine(interm. 53).

EXAMPLE 10

a) 106 Parts of N,N-dimethylformamide were added dropwise to 650 partsof aluminum chloride and the solution was stirred for 15 min at 75° C.There were added portionwise 112 parts of3,4-dihydro-2(1H)-quinazolinethione and, after stirring for 15 min at75° C., 136 parts of 3-pyridinylcarbonyl chloride hydrochloride.Stirring at 75° C. was continued overnight and then the mixture waspoured into 2500 parts of ice-water. The precipitate was filtered offand stirred for 13 hours in a mixture of ice-water and 1530 parts of asodium hydroxide solution 50%. The product was filtered off, washed withwater and dried, yielding 150 parts (82%) of (3-pyridinyl)(1,2,3,4-tetrahydro-2-thioxo-6-quinazolinyl)methanone; (decomp.)(interm. 54).

b) A mixture of 2.7 parts of intermediate (54), 89 parts oftetrahydrofuran, 18.8 parts of N,N-dimethylformamide and 1.45 parts ofiodomethane was stirred for 18 hours at room temperature. The reactionmixture was filtered and the filtrate was neutralized with ammoniumhydroxide. The product was extracted with dichloromethane. The extractwas dried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 95:5). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom 2,2'-oxybispropane. The product was filtered off and dried,yielding 1.75 parts (61.8%) of[3,4-dihydro-2-(methylthio)-6-quinazolinyl](3-pyridinyl)methanone; mp.155.8° C. (interm. 55).

c) To a solution of 8.5 parts of intermediate (55) in 47 parts ofN,N-dimethylformamide there were added 1.4 parts of a dispersion ofsodium hydride in mineral oil (50%). After stirring for 20 min at roomtemperature, there was added dropwise a solution of 6.12 parts of methyl2-bromoacetate in 9.4 parts of N,N-dimethylformamide. Stirring at roomtemperature was continued for 1/2 hour. The reaction mixture was dilutedwith water and the product was extracted with methylbenzene. The organiclayer was in its turn extracted with diluted hydrochloric acid. Theaqueous layer was basified with sodium hydroxide and extracted withmethylbenzene. The extract was dried, filtered and evaporated and theresidue was purified by column chromatography (silica gel; CH₃ C₆ H₅/CH₃ CN 75:25). The eluent of the desired fraction was evaporated andthe residue was crystallized from 1,1'-oxybisethane. The product wasfiltered off and dried, yielding 1.9 parts (13.3%) of methyl3.4-dihydro-2-(methylthio)-6-(3-pyridinylcarbonyl)-3-quinazolineacetate;mp. 113.6° C. (interm. 56).

EXAMPLE 11

a) A mixture of 26.7 parts of ethylN-[[5-(4-methylbenzoyl)-2-nitrophenyl]methyl]glycine (which is aprecursor to intermediate 50 in Example 9), 6.25 parts of hydroxylaminemonohydrochloride, 5.25 parts of potassium fluoride and 395 parts ofethanol was stirred for 22 hours at reflux temperature. The reactionmixture was evaporated and the residue was dissolved in ethyl acetate.The whole was washed with sodium hydrogen carbonate solution 10% andwith water. The organic layer was dried, filtered and evaporated and theresidue was purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃OH 98:2). The eluent of the E- and Z-isomer fractions was evaporated andthe residue was crystallized from 2,2'-oxybispropane, yielding 3.7 partsof product. The mother liquor was evaporated and the residue wasisomerized in a mixture of 1,4-dioxane and 2-propanol, saturated withHCl, by stirring overnight. The solvent was evaporated and the residuewas stirred in water. After neutralizing with NaHCO₃ 10%, the productwas extracted with dichloromethane. The extract was dried, filtered andevaporated and the residue was crystallized from 2,2'-oxybispropane,yielding 2 additional fractions of resp. 3.6 parts and 1.2 parts ofproduct. The three fractions were recrystallized from a mixture of ethylacetate and 2,2'-oxybispropane, yielding 5.3 parts (19%) of ethyl(E)-N-[[5-[(hydroxyimino)(4-methylphenyl)methyl]-2-nitrophenyl]methyl]glycine (interm. 57).

b) To a stirred mixture of 5.3 parts of intermediate (57) in 89 parts oftetrahydrofuran there were added 1.8 parts of 2-methyl-2-propanol,potassium salt and, after 5 min, 0.44 parts ofN,N-di[2-(2-methoxyethoxy)ethyl]-2-(2-methoxyethoxy)ethanamine. Nextthere was added dropwise a solution of 3 parts of2-chloro-N-cyclohexyl-N-methyl-acetamide in 44.5 parts oftetrahydrofuran. Stirring was continued for 3 hours at room temperature.The reaction mixture was evaporated and the residue was taken up inwater. The product was extracted with a mixture of dichloromethane andmethanol (90:10). The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography (silica gel; CH₃ COOC₂ H₅/hexane 50:50). The eluent of the desired fraction was evaporated,yielding 5.7 parts (77.6%) of ethyl(E)-N-[[5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](4-methylphenyl)methyl]-2-nitrophenyl]methyl]glycine(interm 58).

c) A mixture of 5.7 parts of intermediate (58), 2 parts of a solution ofthiophene in methanol 4% and 119 parts of ethanol was hydrogenated atnormal pressure and room temperature with 3 parts ofplatinum-on-charcoal catalyst 5%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated, yielding 5.1 parts (94.6%) of ethyl(E)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](4-methylphenyl)methyl]phenyl]methyl]glycine(interm. 59).

EXAMPLE 12

a) To a stirred and cooled (0° C.; 2-propanone/dry ice) solution of 54.4parts of methyl 5-methyl-2-nitrobenzoate in 405 parts of aceticanhydride and 394 parts of acetic acid were added dropwise 110 parts ofsulfuric acid and portionwise 83.6 parts of chromium(VI)oxide. Stirringwas continued for 1/2 hour at 0°-10° C. and overnight at roomtemperature. The reaction mixture was poured into ice-water and thewhole was treated with dichloromethane. The precipitate which formed,was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at80° C., yielding 30.2 parts (48.1%) of product. The dichloromethanelayer was separated and extracted with a sodium hydrogen carbonatesolution and the aqueous extract was acidified with HCl 2N. Theprecipitate was filtered off and treated similarly as before, yieldingan additional 5 parts (8.0%) of product. Total yield: 35.2 parts (56.1%)of 2-nitro-1,5-benzenedicarboxylic acid, 1-methyl ester; mp. 197.5° C.(interm. 60).

From the dichloromethane layer there was also obtained methyl5-[bis(acetyloxy)methyl]-2-nitrobenzoate; mp. 102.3° C. (interm. 61).

b) To a cooled (-18° C.; 2-propanone/dry ice) solution of 5.63 parts ofintermediate (60) in 44.5 parts of tetrahydrofuran there were addeddropwise 10.7 parts of a solution of dimethylsulfide borane complex intetrahydrofuran 2M. The mixture was allowed to warm to room temperatureand was then refluxed for 2 hours. There were added 23.7 parts ofmethanol and refluxing was continued for 10 min. The reaction mixturewas evaporated and the residue was taken up in 2,2'-oxybispropane. Thissolution was successively washed with water, Na₂ CO₃ 5% and water andwas then dried, filtered and evaporated. The residual syrup was leftovernight to crystallize. The product was recrystallized from2,2'-oxybispropane, filtered off, washed with 2,2'-oxybispropane anddried in vacuo at room temperature, yielding 2.1 parts (39.8%) ofproduct. Evaporation of the mother liquor yielded an additional 1.9parts (36.0%) of product. Total yield: 4.0 parts (75.8%) of methyl 5-(hydroxymethyl)-2-nitrobenzoate; mp. 54.5° C. (interm. 62).

c) A mixture of 1.9 parts of intermediate (62), 7.8 parts ofmanganese(IV)oxide and 133 parts of dichloromethane was stirred overweekend at room temperature. The reaction mixture was filtered overdiatomaceous earth. To the filtrate there was added methylbenzene andthe whole was filtered again. The filtrate was evaporated, yielding 1.42parts (75.4%) of methyl 5-formyl-2-nitrobenzoate; mp. 76.7° C. (interm.63). Hydrolysis of intermediate (61) in an aqueous acidic medium alsoyielded methyl 5-formyl-2-nitrobenzoate (interm. 63).

d) A mixture of 22 parts of intermediate (63), 8.4 parts ofhydroxylamine monohydrochloride and 147 parts of pyridine was heated at80° C. for 2 hours. The solvent was evaporated and the residual oil waspartitioned between water and 2,2'-oxybispropane. The organic layer wasseparated, washed successively with water, HCl 1N, water, NaHCO₃ 5% andwater, and was then dried, filtered and evaporated. The residue wasdried in vacuo at 60° C., yielding 19.8 parts (80.3%) of methyl(E)-5-[(hydroxyimino)methyl]-2-nitrobenzoate; mp. 116.0° C. (interm.64).

e) To a refluxing mixture of 18.3 parts of intermediate (64), 12.37parts of sodium tetrahydroborate and 320 parts of tetrahydrofuran therewere added dropwise 56.9 parts of methanol. After refluxing for 1 hour,the reaction mixture was poured into ice-water. The whole was acidifiedwith hydrochloric acid 2N and then extracted with dichloromethane. Theextract was washed successively with water, NaHCO₃ 5% and water, and wasthen dried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH/THF 90:5:5). The eluent ofthe desired fraction was evaporated and the residue was washed with2,2'-oxybispropane and dried in vacuo at 60° C., yielding 12.6 parts(78.6%) of (E)-3-(hydroxymethyl)-4-nitro-benzaldehyde, oxime; mp. 128.9°C. (interm. 65).

EXAMPLE 13

a) To a stirred mixture of 58.9 parts of potassium acetate, 100.5 partsof ethyl glycine monohydrochloride and 790 parts of ethanol, there wereadded 100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (preparedfollowing the procedure described in Example 9 or Example 14. Afterstirring for 1/2 hour, there were added portionwise 9.4 parts of sodiumcyanotrihydroborate. Stirring was continued for 1/2 hour at roomtemperature. The reaction mixture was evaporated and the residue waspartitioned between water and dichloromethane. The organic layer wasseparated, washed with water, dried, filtered and evaporated. Theresidue was purified by column chromatography (silica gel; CH₂ Cl₂ /C₂H₅ OH 99:1). The eluent of the desired fraction was evaporated, yielding71 parts (56.2%) of ethylN-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66).

b) A mixture of 68 parts of intermediate (66), 14 parts of hydroxylaminemonohydrochloride, 11.6 parts of potassium fluoride and 790 parts ofethanol was stirred for 3 hours at reflux temperature. After cooling,the reaction mixture was filtered. The precipitate was rinsed withethanol and the combined filtrates were evaporated. The residue wastaken up in a mixture of ethyl acetate and water and the whole wasneutralized with NaHCO₃ 10%. The organic layer was separated, washedwith water, dried, filtered and evaporated, yielding 51.4 parts ofproduct (E/Z isomer mixture) (1). From the aqueous layer, a precipitatewas filtered off, which was washed with 2,2'-oxybispropane and dried invacuo at 60° C., yielding an additional 8.7 parts of product (mainlyZ-isomer) (2). Total yield: 60.1 parts (86.1%) of (E/Z) isomer mixture,which can be separated by column chromatography. A fraction of (1) wascrystallized from 2-propanone to obtain a small amount of pure ethyl(E)-N-[[5-[(3-bromophenyl)(hydroxyimino)methyl]-2-nitrophenyl]methyl]glycine; mp. 131.2° C.(interm. 68). Crystallization of (2) from ethyl acetate yielded a smallamount of pure ethyl (Z)-N-[[5-[(3-bromophenyl)(hydroxyimino)methyl]-2-nitrophenyl]methyl]glycine; mp. 149.8° C.(interm. 67).

c) To a stirred solution of 5.3 parts of intermediate (68) in 89 partsof tetrahydrofuran there were added 1.46 parts of 2-methyl-2-propanol,potassium salt and, after 5 min, 0.38 parts of2-(methoxyethoxy)-N,N-bis[2-(methoxyethoxy)ethyl]ethanamine and asolution of 2.46 parts of chloro-N-cyclohexyl-N-methylacetamide in sometetrahydrofuran. Stirring was continued for 20 min. The reaction mixturewas evaporated and the residue was stirred in water. The product wasextracted with a mixture of ethanol and dichloromethane (10:90). Theextract was dried, filtered and evaporated and the residue was purifiedby column chromatography (silica gel; hexane/CH₃ COOC₂ H₅ 50:50). Theeluent of the desired fraction was evaporated and the residue wasco-evaporated with methylbenzene, yielding 5 parts (70.7%) of ethyl(E)-N-[[5-[(3-bromophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]methyl]-2-nitrophenyl]methyl]glycine(interm. 69).

d) A mixture of 5 parts of intermediate (69), 2 parts of a solution ofthiophene in methanol 4% and 158 parts of ethanol was hydrogenatedovernight at normal pressure and room temperature with 2 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was co-evaporated with methylbenzene,yielding 4.6 parts (96.7%) of ethyl(E)-N-[[2-amino-5-[(3-bromophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]methyl]phenyl]methyl]glycine(intermediate 70). In a similar manner there were also prepared:

ethyl(Z)-N-[[2-amino-5-[[[(3-bromophenyl)-2-(cyclohexylmethylamino)-2-oxoethoxy]imino]methyl]phenyl]methyl]glycine(interm. 71);

ethyl(E)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino][4-(trifluoromethyl)phenyl]methyl]phenyl]methyl]glycine(interm. 72);

ethyl(E+Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](3-methylphenyl)methyl]phenyl]methyl]glycine(interm. 73);

ethyl(Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](3-methylphenyl)methyl]phenyl]methyl]glycine(interm. 74);

ethyl(Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino][4-(trifluoromethyl)phenyl]methyl]phenyl]methyl]glycine(interm. 75);

ethyl(Z)-N-[[2-amino-5-[(3-chlorophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]methyl]phenyl]methyl]glycine(interm. 76);

ethyl(E)-N-[[2-amino-5-[(3-chlorophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]methyl]phenyl]methyl]glycine(interm. 77);

ethyl(E)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](3-methoxyphenyl)methyl]phenyl]methyl]glycine(interm. 78); and

ethyl(Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](2-thienyl)methyl]phenyl]methyl]glycine(interm. 79).

EXAMPLE 14

a) 81.6 Parts of a dispersion of sodium hydride in mineral oil (50%)were stirred in hexane to remove the oil. The solvent was decanted andto the residue there were added 825 parts of dimethyl sulfoxide. Whilestirring at room temperature, there were added dropwise a solution of92.3 parts of 2-thiopheneacetonitrile in 138 parts of dimethyl sulfoxide(when necessary, cooling on ice) and next a solution of 173.7 parts ofintermediate (43) in 138 parts of dimethyl sulfoxide. Stirring at roomtemperature was continued overnight. The crude reaction mixture was usedas such for further synthesis. Yield: 238.8 parts (100%) ofα-[3-(dimethoxymethyl)-4-nitrophenyl]-2-thiopheneacetonitrile (interm.80).

b) A mixture of 238.8 parts of intermediate (80), 40.8 parts of adispersion of sodium hydride in mineral oil (50%) and 1100 parts ofdimethyl sulfoxide was stirred at room temperature, while air wasbubbled through for a week and oxygen for 40 hours. The reaction mixturewas poured into ice-water and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was stirred in water and the whole was re-extracted withdichloromethane. The extract was dried, filtered and evaporated and theresidue was purified by column chromatography (silica gel; CH₂ Cl₂). Theeluent of the desired fraction was evaporated, yielding 181.5 parts(78.7%) of [3-(dimethoxymethyl)-4-nitrophenyl](2-thienyl)methanone(interm. 81).

c) A mixture of 181.5 parts of intermediate (81), 468 parts of2-propanol saturated with hydrochloric acid, 371 parts of 1,4-dioxaneand 240 parts of water was stirred for 18 hours at reflux temperature.After cooling, the precipitate was filtered off, washed with 2-propanoland 2,2'-oxybispropane and dried, yielding 89.7 parts (58.2%) ofproduct. The filtrate was concentrated to obtain further precipitation.The precipitate was filtered off, washed successively with 2-propanol,diluted NH₄ OH, water, 2-propanol and 2,2'-oxybispropane, and dried,yielding an additional 25.4 parts (16.5%) of product. Total yield: 115.1parts (74.7%) of 2-nitro-5-(2-thienylcarbonyl)benzaldehyde (interm. 82).

In a similar manner there was also prepared2-nitro-5-[4-(trifluoromethyl)benzoyl]benzaldehyde; mp. 119.5° C.(interm. 83)

B. Preparation of the final compounds EXAMPLE 15

To a stirred and cooled (0°-5° C.) solution of 3.19 parts ofintermediate (7) in 40 parts of ethanol there was added dropwise asolution of 1.13 parts of bromocyanide in 8 parts of ethanol. Stirringwas continued overnight at room temperature and for 3 hours at refluxtemperature. After cooling, the reaction mixture was treated withmethanol, saturated with ammonia. The precipitate was filtered off,washed with ethanol, stirred in water and boiled in ethanol. The impureproduct was filtered off, washed with ethanol and 2,2'-oxybispropane andrecrystallized from a mixture of 16 parts of methanol and 75 parts ofN,N-dimethylformamide. The product was filtered off, washed withmethanol and 2,2'-oxybispropane and dried in vacuo at 70°-75° C.,yielding 1.08 parts (36.3%) of7-benzoyl-3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one; mp.>300° C.(comp. 1).

EXAMPLE 16

To a stirred and cooled (0° C.) solution of 9.5 parts of intermediate(25) in 160 parts of ethanol there was added dropwise a solution of 2.08parts of bromocyanide in ethanol. Stirring was continued for 1 1/2 hourat 0° C., for 1 hour at room temperature and for 2 hours at refluxtemperature. The reaction mixture was evaporated and the residue waspartitioned between NaCl (sat.) and dichloromethane. Afterneutralization with a sodium hydroxide solution, the product wasextracted with dichloromethane. The extract was dried, filtered andevaporated. The residue was purified twice by column chromatography(silica gel; CHCl₃ /CH₃ OH/CH₃ OH(NH₃) 98:1:1; HPLC; silica gel; CHCl₃/CH₃ OH 93:7). The first and second fraction were separately evaporatedand the residues were crystallized from ethyl acetate. The productsobtained from both fractions were filtered off, washed with ethylacetate and 2,2'-oxybispropane and dried in vacuo at 60° C., yieldingresp. 2.92 parts (32.2%) of (Z)-N-cyclohexyl-N-methyl-2-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]-oxy]acetamide;mp. 173.4° C. (comp. 10) and 2.4 parts (26.3%) of(E)-N-cyclohexyl-N-methyl-2-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]acetamide;mp. 202.2° C. (comp. 9).

EXAMPLE 17

To a stirred suspension of 16 parts of compound (1) in 440 parts ofpyridine there were added 4.17 parts of hydroxylamine monohydrochloride.Stirring was continued for 4 hours at reflux temperature. Theprecipitate was filtered off (*), washed with pyridine, stirred in waterand washed successively with water, 2-propanol and 2,2'-oxybispropane.The product was filtered off and dried in vacuo at 100° C., yielding afirst fraction of 9.6 parts (57.1%) of product (E/Z=75/25); mp.>300° C.The filtrate (*) was evaporated and the residue was treated in the samemanner as the precipitate hereinbefore, yielding an additional 5.5 parts(32.7%) of product. Total yield: 15.1 parts (89.8%) of(E+Z)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2(1H)-one(comp. 2).

EXAMPLE 18

A mixture of 2.01 parts of compound (2), 6 parts of 2-propanol,saturated with hydrochloric acid and 62 parts of 1,4-dioxane was stirredfor 4 hours at room temperature. Gaseous hydrogen chloride was bubbledthrough the reaction mixture, while cooling in an ice-bath. Stirring wascontinued overnight at room temperature. The precipitate was filteredoff, washed with 2,2'-oxybispropane and stirred in water. The aqueouslayer was treated with an ammonium hydroxide solution and stirred for 10min. The precipitate filtered off, washed with water and purified bycolumn chromatography (HPLC; silica gel; H₂ O/CH₃ OH (0.5% (NH₄)₂ CO₃)).The eluent of the desired fractions was evaporated and the residue wasstirred in water. The product was filtered off, washed with water anddried in vacuo at 70°-90° C., yielding 0.867 parts (41.3%) of(E)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2(1H)-one;mp.>300° C. (comp. 3).

EXAMPLE 19

a) A mixture of 8.5 parts of compound (2), 110 parts of dimethylsulfoxide, 8.36 parts of 1,1-dimethylethylchlorodimethylsilane and 7.56parts of 1H-imidazole was stirred for 10 min at 60° C. The reactionmixture was poured into 500 parts of water and the whole was extractedwith 2,2'-oxybispropane. The extract was dried, filtered and evaporated.The residue was crystallized from methanol, washed with methanol anddried, yielding a first fraction of 7.1 parts (60.9%) of product.Evaporation of the mother liquor yielded an additional 4.6 parts (39.5%)of product.

Total yield: 11.7 parts (≈100%) of(E+Z)-7-[[[(1,1-dimethylethyl)dimethylsiloxy]imino]phenylmethyl]-3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one;mp. 254.7° C. (comp. 5).

b) Compound (5) was separated into its pure E and Z isomers by columnchromatography (HPLC; silicagel γ-aminopropyl; (C₂ H₅)₂ O)/CH₃ CN/THF/H₂O 46.5:5:46.5:2). The eluent of the separated E- and Z-isomer fractionswas evaporated and the residues were chromatographed again (HPLC;γ-aminopropyl; CH₂ Cl₂ /CH₃ OH 96:4). The products were dried in vacuo,yielding 3.3 parts (19.7%) of(E)-7-[[[[(1,1-dimethylethyl)dimethylsilyl]oxy]imino]phenylmethyl]-3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one;mp. 221.0° C. (comp. 18) and 0.9 parts (5.4%) of(Z)-7-[[[[(1,1-dimethylethyl)dimethylsilyl]oxy]imino]phenylmethyl]-3,5-dihydroimidazo[2,1-b]-quinazolin-2(1H)-one;mp.>250° C. (decomp.) (comp. 19).

c) To a mixture of 0.103 parts of compound (19) and 4.45 parts oftetrahydrofuran there were added 0.53 parts of a solution oftetrabutylammonium fluoride in tetrahydrofuran 1M. After stirring for 10min at room temperature, the reaction mixture was evaporated and theresidue was taken up in water. The solid was filtered off, washed withwater and boiled in methanol. The product was filtered off, washed withmethanol and 2,2'-oxybispropane and dried in vacuo at 80° C., yielding0.033 parts (35.9%) of(Z)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2(1H)-one;mp.>250° C. (comp. 15).

EXAMPLE 20

a) A solution of 0.3 parts of compound (6), 2.5 parts of a sodiumhydroxide solution 1N and 2 parts of methanol was stirred for 1 hour atroom temperature. There were added 2.5 parts of a hydrochloric acidsolution 1N. The precipitated product was filtered off, washed withwater and methanol and crystallized from methanol. The product wasfiltered off, washed with methanol and 2,2'-oxybispropane and dried invacuo at 60° C., yielding 0.15 parts (53.7%) of(E+Z)-2-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]aceticacid; mp. 253.0° C. (E/Z=75/25) (comp. 7).

b) Compound 56 was prepared from compound 37 in a similar manner, butwithout organic solvent (methanol) and with stirring at 60° C. for 1hour.

EXAMPLE 21

a) A mixture of 10.7 parts of compound (28), 78.4 parts of a sodiumhydroxide solution 1N and 59.3 parts of ethanol was stirred overnight atroom temperature. The aqueous layer was extracted with dichloromethaneand then acidified to pH 5 with HCl 2N. The product was filtered off,washed with water, co-evaporated with a mixture of methanol andmethylbenzene and with methylbenzene, boiled in methanol, washed with amixture of methanol and 2,2'-oxybispropane and dried at 60° C., yielding2.1 parts (21.4%) of(E+Z)-4-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]butanoicacid; mp. 268.5° C. (comp. 31).

b) To a stirred solution of 1.9 parts of compound (31) in 303 parts ofdimethyl sulfoxide there were added 1.5 parts of1,1'-carbonylbis[1H-imidazole]. After stirring for 10 min at roomtemperature, for 2 hours at 60° C. and for 1/2 hour at 80° C., therewere added 4.7 parts of N-methylcyclohexanamine. Stirring was continuedovernight at 80° C. The reaction mixture was poured into water and thewhole was acidified to pH 5 with acetic acid 10%. The product wasextracted with dichloromethane and the extract was washed with water,dried, filtered and evaporated. The residue was purified twice by columnchromatography (silica gel; CH₃ COOC₂ H₅ /CH₃ OH 95:5; CH₂ Cl₂ /CH₃ OH95:5). The eluent of the desired fraction was evaporated and the residuewas co-evaporated with methylbenzene. The E and Z isomers were separatedby HPLC (Licroprep amino; CHCl₃). The two fractions were evaporated andthe residues stirred in water and dried in vacuo at 70° C., yielding0.05 parts (2.1%) of(E)-N-cyclohexyl-N-methyl-4-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]butanamide(comp. 33) and 0.03 parts (1.3%) of(Z)-N-cyclohexyl-N-methyl-4-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]butanamide(comp. 34).

EXAMPLE 22

A mixture of 1.96 parts of intermediate (56), 20 parts of ammoniumacetate and 2.1 parts of acetic acid was stirred for 45 min at 130° C.The reaction mixture was diluted with water. The precipitate wasfiltered off, stirred in N,N-dimethylformamide and methanol and was thendissolved in 20 ml of formic acid. After filtration, there was addedtetrahydrofuran to enhance precipitation. The product was filtered offand dried in vacuo at 85° C., yielding 0.9 parts (56.0%) of1,5-dihydro-7-(3-pyridinylcarbonyl)imidazo[2,1-b]quinazolin-2(3e,uns/H/)-one; mp. 275.1° C. (comp. 39).

EXAMPLE 23

To a mixture of 1 part of compound (65) and 9.4 parts ofN,N-dimethylformamide there were added dropwise 0.4 parts of thionylchloride. After stirring for 5 min, there were added at once 2.03 partsof N-methylcyclohexanamine. The whole was stirred for 5 min and was thenevaporated. The residue was stirred in water, filtered off and purifiedby column chromatography (silica gel; CHCl₃ /CH₃ OH 95:5). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom 2-propanol. The product was filtered off, washed with 2-propanoland 1,1'-oxybisethane and dried, yielding 0.4 parts (31.1%) of(E)-N-cyclohexyl-3-(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)-N-methyl-3-phenyl-2-propenamide;mp. 204° C. (decomp.) (comp. 67).

EXAMPLE 24

a) 133 Parts of dichloromethane were stirred while gaseous hydrochloricacid was bubbled through for 1 min. There were added portionwise 4.6parts of compound (59) and gaseous hydrochloric acid was passed throughfor 1 more min. After the dropwise addition of 1.36 parts of thionylchloride, the whole was stirred at reflux temperature for 40 min. Thereaction mixture was evaporated and the residue was co-evaporated withmethylbenzene, yielding 4.9 parts (94.0%) of(E+Z)-5-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]pentanoylchloride monohydrochloride (interm. 84).

b) To a stirred solution of 6.0 parts of N-methylcyclohexanamine and 160parts of dichloromethane there were added portionwise 5.9 parts ofintermediate (84). Stirring was continued for 1 hour at roomtemperature. The reaction mixture was poured into water and the productwas extracted with dichloromethane. The extract was washed with water,dried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH 92.5:7.5) and then separatedinto its E and Z isomers by HPLC (silica gel; γ-aminopropyl;c.hexane/(C₂ H₅)₂ O/CH₃ OH/H₂ O 45:45:10:1). The E isomer fraction wascrystallized from 2-propanol. The product was filtered off, washed with2,2'-oxybispropane and dried in vacuo at 50° C., yielding 0.12 parts(1.81%) of(E)-N-cyclohexyl-N-methyl-5-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]pentanamide;mp. 189.9° C. (comp. 61). The Z isomer fraction was stirred in2,2'-oxybispropane. The product was filtered off, washed with2,2'-oxybispropane and dried in vacuo at 40° C., yielding 0.42 parts(6.23%) of(Z)-N-cyclohexyl-N-methyl-5-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]amino]oxy]pentanamidehemihydrate; mp. 104.1° C. (comp. 60).

All compounds listed in Tables 1 and 2 were prepared following methodsof preparation described in Examples 15-24, as is indicated in thecolumn Ex. No.

                                      TABLE 1                                     __________________________________________________________________________     ##STR33##                                                                    Comp                                                                              Ex                                                                        No. No.                                                                              R        X                R.sup.1                                                                          Physical Data                             __________________________________________________________________________     1  15 C.sub.6 H.sub.5                                                                        O                H  mp. >300° C.                        2  17 C.sub.6 H.sub.5                                                                        NOH              H  (E + Z)/mp. >300° C. (dec.)         3  18 C.sub.6 H.sub.5                                                                        NOH              H  (E)/mp. 279.7° C.                   4  17 C.sub.6 H.sub.5                                                                        NOCH.sub.3       H  (E + Z)/mp. 265.0° C. (dec.)        5  19a                                                                              C.sub.6 H.sub.5                                                                        NOSi(CH.sub.3).sub.2 (t-C.sub.4 H.sub.9)                                                       H  (E + Z)/mp. 254.7° C.               6  16 C.sub.6 H.sub.5                                                                        NOCH.sub.2 COOC.sub.2 H.sub.5                                                                  H  (E + Z)/mp. 251.7° C.               7  20a                                                                              C.sub.6 H.sub.5                                                                        NOCH.sub.2 COOH  H  (E +  Z)/mp. 253.0° C.              8  16 C.sub.6 H.sub.5                                                                         ##STR34##       H  (E + Z)/HCl/1/2(CH.sub.3).sub.2 CHOH                                          mp. 169.8° C.                       9  16 C.sub.6 H.sub.5                                                                         ##STR35##       H  (E)/mp. 202.2° C.                  10  16 C.sub.6 H.sub.5                                                                         ##STR36##       H  (Z)/mp. 173.4° C.                  11  15 C.sub.6 H.sub.5                                                                        O                CH.sub.3                                                                         mp. >300° C.                       12  15 4-CH.sub.3 OC.sub.6 H.sub.4                                                            O                H  mp. 260° C. (dec.)                 13  17 4-CH.sub.3 OC.sub.6 H.sub.4                                                            NOH              H  (E + Z)/1/2 H.sub.2 O                                                         mp. 290.8° C.                      14  15 4-FC.sub.6 H.sub.4                                                                     O                H  mp. >300° C. (dec.)                15  19c                                                                              C.sub.6 H.sub.5                                                                        NOH              H  (Z)/mp. >250° C.                   16  17 4-BrC.sub.6 H.sub.4                                                                    NOH              H  (E + Z:55/45)/mp. >300° C.         17  15 4-BrC.sub.6 H.sub.4                                                                    O                H  mp. >300° C.                       18  19b                                                                              C.sub.6 H.sub.5                                                                        NOSi(CH.sub.3).sub.2 (t-C.sub.4 H.sub.9)                                                       H  (E)/mp. 221° C.                    19  19b                                                                              C.sub.6 H.sub.5                                                                        NOSi(CH.sub.3).sub.2 (t-C.sub.4 H.sub.9)                                                       H  (Z)/mp. >250.0° C.                 20  15 4-CH.sub.3 C.sub.6 H.sub.4                                                             O                H  mp. >300° C. (dec.)                21  15 3-CH.sub.3 OC.sub.6 H.sub.4                                                            O                H  mp. 280° C.                        22  17 4-FC.sub.6 H.sub.4                                                                     NOH              H  (E + Z)/mp. 274.2° C.              23  17 4-CH.sub.3 C.sub.6 H.sub.4                                                             NOH              H  (E + Z)/mp. 271.2° C.              24  15 3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                 O                H  mp. >300° C.                       25  17 3-CH.sub.3 OC.sub.6 H.sub.4                                                            NOH              H  (E + Z)/mp. >300° C.               26  17 3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                 NOH              H  (E + Z)/mp. 216.6° C.              27  15 4-ClC.sub.6 H.sub.4                                                                    O                H  mp. 260° C. (dec.)                 28  16 C.sub.6 H.sub.5                                                                        NO(CH.sub.2).sub.3 COOC.sub.2 H.sub.5                                                          H  (E + Z)/mp. 190.0° C.              29  17 4-ClC.sub.6 H.sub.4                                                                    NOH              H  (E + Z)/1/2 H.sub.2 O/                                                        mp. >300° C. (dec.)                30  16 C.sub.6 H.sub.5                                                                         ##STR37##       H  (E)/mp. 151.2° C.                  31  21a                                                                              C.sub.6 H.sub.5                                                                        NO(CH.sub.2).sub.3 COOH                                                                        H  (E + Z)/mp. 268.5° C.              32  16 C.sub.6 H.sub.5                                                                        CHCOOC.sub.2 H.sub.5                                                                           H  mp. 228.6° C.                      33  21b                                                                              C.sub.6 H.sub.5                                                                         ##STR38##       H  (E)                                       34  21b                                                                              C.sub.6 H.sub.5                                                                         ##STR39##       H  (Z)                                       35  16 4-BrC.sub.6 H.sub.4                                                                     ##STR40##       H  (E)/mp. 229.3° C.                  36  16 C.sub.6 H.sub.5                                                                        NO(CH.sub.2).sub.4 COOC.sub.2 H.sub.5                                                          H  (E + Z)/mp. 139.8° C.              37  16 C.sub.6 H.sub.5                                                                        NO(CH.sub.2).sub.2 COOC.sub.2 H.sub.5                                                          H  (E + Z)/mp. 185.2° C.              38  16 4-FC.sub.6 H.sub.4                                                                      ##STR41##       H  (E)/3/2H.sub.2 O/mp. 205.6°                                            C.                                        39  22 3-pyridinyl                                                                            O                H  mp. 275.1° C.                      40  17 3-pyridinyl                                                                            NOH              H  (E + Z)/1/2H.sub.2 O/mp.                                                      279.4° C.                          41  16 4-FC.sub.6 H.sub.4                                                                      ##STR42##       H  (E + Z)/1/2H.sub.2 O/mp.                                                      240.2° C.                          42  16 4-CH.sub.3 C.sub.6 H.sub.4                                                              ##STR43##       H  (E)/1/2H.sub.2 O/mp. 189.3°                                            C.                                        43  16 3-BrC.sub.6 H.sub.4                                                                     ##STR44##       H  (E)/1/2H.sub. 2 O/mp. 198.4°                                           C.                                        44  16 3-BrC.sub.6 H.sub.4                                                                     ##STR45##       H  (Z)/1/2H.sub.2 O/mp. 200.0°                                            C.                                        45  16 H                                                                                       ##STR46##       H  (E)/mp. 241° C.                    46  16 4-ClC.sub.6 H.sub.4                                                                     ##STR47##       H  E/1/2H.sub.2 O/mp. 207.4° C.       47  16 4-CF.sub.3 C.sub.6 H.sub.4                                                              ##STR48##       H  Z/mp. 195.8° C.                    48  16 4-CF.sub.3 C.sub.6 H.sub.4                                                              ##STR49##       H  E/mp. 229.7° C.                    49  16 3-CH.sub.3 OC.sub.6 H.sub.4                                                             ##STR50##       H  Z/1/2H.sub.2 O/mp. 155.2° C.       50  16 3-ClC.sub.6 H.sub. 4                                                                    ##STR51##       H  Z/1/2H.sub.2 O/mp. 216.7° C.       51  16 3-ClC.sub.6 H.sub.4                                                                     ##STR52##       H  E/1/2H.sub.2 O/mp. 189.4° C.       52  16 3-CH.sub.3 OC.sub.6 H.sub.4                                                             ##STR53##       H  E/1/2H.sub.2 O/mp. 169.9° C.       53  16 2-thienyl                                                                               ##STR54##       H  (E + Z)/mp. 204.9° C.              54  16 3-CH.sub.3 C.sub.6 H.sub.4                                                              ##STR55##       H  E/H.sub.2 O/mp. 150.0° C.          55  16 3-CH.sub.3 C.sub.6 H.sub.4                                                              ##STR56##       H  Z/1/2H.sub.2 O/mp. 161.0° C.       56  20b                                                                              C.sub.6 H.sub.5                                                                        NO(CH.sub.2).sub.2 COOH                                                                        H  (E + Z)                                   57  24 C.sub.6 H.sub.5                                                                         ##STR57##       H  Z/1/2H.sub.2 O/mp. 186.7° C.       58  24 C.sub.6 H.sub.5                                                                         ##STR58##       H  E/1/2H.sub.2 O/mp. 140.8° C.       59  21a                                                                              C.sub.6 H.sub.5                                                                        NO(CH.sub.2).sub.4 COOH                                                                        H  (E + Z)                                   60  24b                                                                              C.sub.6 H.sub.5                                                                         ##STR59##       H  Z/1/2H.sub.2 O/mp. 104.1° C.       61  24b                                                                              C.sub.6 H.sub.5                                                                         ##STR60##       H  E/mp. 189.9° C.                    __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     ##STR61##                                                                    Comp                                                                              Ex.                                                                       No. No.                                                                              X           R.sup.1                                                                          R.sup.2                                                                          Physical Data                                        __________________________________________________________________________    62  16 CHCOOC.sub.2 H.sub.5                                                                      H  H  (Z)/mp. 259.9° C.                             63  16 CHCOOC.sub.2 H.sub.5                                                                      H  H  (E)/mp. 279.2° C.                             64  21a                                                                              CHCOOH      H  H  (Z)/mp. >300° C.                              65  21a                                                                              CHCOOH      H  H  (E)/                                                 66  23                                                                                ##STR62##  H  H  (Z)/1/2H.sub.2 O/mp. 219.4° C.                67  23                                                                                ##STR63##  H  H  (E)/mp. 204° C.                               68  15 O           CH.sub.2 CH.sub.2                                                                   mp. >300° C.                                  69  17 NOH         CH.sub. 2 CH.sub.2                                                                  (E + Z)/mp. >300° C.                          70  15 O           CH.sub.3                                                                         CH.sub.3                                                                         mp. >300° C.                                  71  17 NOH         CH.sub.3                                                                         CH.sub.3                                                                         (E + Z)/mp. 295.0° C.                         __________________________________________________________________________

C) Pharmacological examples

The positive inotropic and lusitropic effect of the instant compoundswere assessed by an in vitro assay system to detect inhibiting effect onthe phosphodiesterase type III_(c) and in an in vivo experiment inclosed-chest anaestetized dogs by monitoring cardiac and haemodynamiceffects of an intravenous infusion of the instant compounds.

EXAMPLE 25 Inhibition of Phosphodiesterase type III_(c) (PDE III_(c)).

The incubation mixture (pH 7.1) (200 μl) contained 50 mM4-morpholinopropanesulfonic acid (MOPS), 1 mMethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA), 6 mM magnesiumchloride, 0.25 mg/ml bovine serum albumin, 1.2 μM ³ H-cAMP (310mCi/mmole) and the phosphodiesterase type III_(c), and was prepared bydilution with water of a stock solution of MOPS, EGTA, MgCl₂, BSA and ³H-cAMP (50 μl) and 2 to 50 μl of a solution of phosphodiesterase typeIII_(c), depending on the enzymatic activity. A protein concentrationwas chosen that showed a linear increase of phosphodiesterase activityduring an incubation period of 10 minutes at 37° C.

When the effect of different compounds on phosphodiesterase activity wastested, the medium without cAMP was incubated with the compound(s) orits carrier (DMSO-1% final concentration) for 5 min. The enzymaticreaction was started by addition of

³ H-cAMP and stopped 10 min later after transferring the tubes in awaterbath at 100° C. for 40 sec. After cooling to room temperature,alkaline phosphatase (0.25 μg/ml) was added and the mixture was left atroom temperature for 20 min. The mixture was subsequently applied to a 1ml DEAE-Sephadex A-25 column (pasteur pipet) and washed twice with 3 ml20 mM Tris-HCl at pH 7.4. The ³ H-labelled reaction products in theeluate were quantified by liquid scintillation counting.

The inhibiting effect of the present compounds on canine heart and humanplatelet phosphodiesterase PDE III_(c) was measured at differentconcentrations of the instant compounds. The IC₅₀ values were calculatedgraphically from the thus obtained inhibition values. Table 3 showsavailable IC₅₀ values of the present compounds on canine heart and humanplatelet PDE III_(c).

                  TABLE 3                                                         ______________________________________                                                       Canine heart                                                                              Human Platelet                                            Comp.   PDE III.sub.c                                                                             PDE III.sub.c                                             No.     IC.sub.50 (10.sup.-6 M)                                                                   IC.sub.50 (10.sup.-6 M)                            ______________________________________                                                  1        0.55        --                                                       2        0.44        0.19                                                     3        0.44        0.19                                                     4        0.37        --                                                       5        0.06        --                                                       6        0.46        0.38                                                     8        0.17         0.058                                                   9        0.064        0.025                                                  10        0.21        0.14                                                    12        0.28        --                                                      13        0.36        --                                                      14        0.49        0.52                                                    15        0.34        --                                                      16        0.26        --                                                      17        0.36        --                                                      20        0.21        --                                                      21        0.145       --                                                      22        0.41        --                                                      23        0.23        --                                                      24        0.19        0.34                                                    25        0.20        --                                                      26        0.19        --                                                      27        0.30        --                                                      28        0.22        --                                                      29        0.19        --                                                      30        0.14        --                                                      31        0.62        --                                                      32        0.26         0.084                                                  33        0.047       --                                                      34        0.78        --                                                      35        0.051       --                                                      36        0.09        --                                                      37        0.12        --                                                      38        0.076       --                                             R 85.906 40        0.93        --                                             R 86.134 41        0.12        --                                             R 86.260 42        0.081       --                                             R 86.313 43        0.15        --                                             R 86.282 44        0.045       --                                             R 86.251 45        0.025       --                                             R 86.275 46        0.067       --                                             R 86.325 48        0.74        --                                             R 86.388 49        0.041       --                                             R 86.620 52        0.04        --                                             R 86.662 53        0.01        --                                             R 86.756 54        0.15        --                                             R 86.759 55        0.089       --                                             R 86.838 57        0.15        --                                             R 86.839 58        0.05        --                                             R 86.856 60        0.24        --                                             R 86.847 61        0.1         --                                             R 86.033 62        0.49        --                                             R 86.130 63        0.38        --                                             R 86.399 65        0.65        --                                             R 86.400 67        0.39        --                                             ______________________________________                                         -- = not yet tested                                                      

EXAMPLE 26 Positive inotropy and lusitropy, blood pressure and heartrate in dogs.

Compound (9) was dissolved in 20% hydroxypropyl beta cyclodextrine etherslightly acidified with 1N HCl, in a concentration of 1 mg.ml⁻¹ (pH5.5). The experiments were performed on 7 mongrel dogs of either sex andvarying age, ranging in body weight from 27 to 33 kg (median 30 kg). Theanimals were intravenously anaesthetized with a mixture of 0.015 mg.kg⁻¹scopolamine and 0.05 mg.kg⁻¹ lofentanil. The animals were intubated witha cuffed endotracheal tube. Intermittent positive pressure ventilationwas performed with a mixture of pressurized air and oxygen (60/40),using a volume-controlled ventilator (Siemens Elema). In the controlperiod the CO₂ concentration in the expired air (ET CO₂), as determinedwith a capnograph (Gould Godart), was kept at 5 vol % by adjustment ofthe respiratory volume (resp. rate=20 breaths,min⁻¹). A continuousintravenous infusion of 0.5 mg.kg⁻¹.h⁻¹ of etomidate was startedimmediately after induction. Body temperature was monitored with athermistor positioned in the pulmonary artery. To prevent blood clottingheparine, 1000 IU.kg⁻¹ i.v., was administered.

The electrocardiogram (ECG) was derived from limb leads (standard lead2). Left ventricular (LVP) and ascending aortic blood pressure (AoP)were measured by retrograde catheterisation via the femoral arterieswith high fidelity cathetertip micromanometers (Honeywell). The otherfemoral vein was cannulated for injection of saline at room temperatureinto the right atrium and for injection of compound (9). Peak ascendingaortic blood flow velocity was measured through the right carotid arterywith an electromagnetic catheter-tip probe connected to a square waveelectromagnetic flow meter (Janssen Scientific Instruments). Thefollowing variables -inter alia-were calculated on-line, usually at 1min intervals: heart rate (HR), diastolic (AoPd) aortic blood pressure,left ventricular end-diastolic pressure (LVEDP), the maximum positiveand maximum negative rate of change of isovolumic LVP (LV dp/dt_(max)and _(min), respectively), the maximum positive first derivative dividedby the actually developed pressure in the left ventricle (LV dp/dt_(max)/Pd). The time constant (T) of relaxation was measured with the use ofan exponential analysis that also estimated the asymptote. After arecorded control period of 20 min the intravenous infusion of compound(9) was started at a rate of 0.005 mg.kg⁻¹ over 120 min. In the wash-outperiod the effects were followed for 75 min.

Compound (9) has positive inotropic properties, starting after 10 min ofinfusion (0.05 mg.kg⁻¹ total dose), as indicated by the pronounced andsignificant increase in the variables related to cardiac performance (LVdp/dt_(max), LV dp/dt_(max) /Pd), in the presence of no change or even aslight decrease in left ventricular end-diastolic pressure (preload) andno change in heart rate. Compound (9) has positive lusitropicproperties, as evidenced by the significant decrease in the timeconstant of relaxation starting after 10 min of infusion (0.05 mg.kg⁻¹total dose). Systemic and pulmonary peripheral vascular resistancedecrease significantly starting after 20 min of infusion of the compound(0.10 mg.kg⁻¹ total dose). This indicates that compound (9) has alsoadditional systemic and pulmonary vasodilatory properties. Thisunloading of the heart occurs without altering heart rate, but withconcomitant increase in cardiac output. These positive inotropic andlusitropic, and vasodilatory effects of the compound (9) arelong-lasting, since the changes in the variables last for more than 75min after stopping the infusion of a total dose of 0.60 mg.kg⁻¹.

following the same procedure, a dose-related increase in cardiacinotropy and lusitropy associated with a dose-related systemicvasodilation and an increase in cardiac output, without changing theheart rate, was observed upon slow infusion (0.005 mg kg⁻¹ min⁻¹) ofcompound (3) for two hours and lasted for more than 90 minutes afterstopping the infusion.

Table 4 shows the % changes in haemodynamic variables measured aftercumulative intravenous bolus administration of some of the presentcompounds in mongrel dogs (maximum end-dose is shown in mg kg⁻¹). Thevariable AoPd (diastolic aortic blood pressure) shows the decrease inblood pressure (vasodilation), HR the influence of the present compoundson the heart rate, LV dp/dt_(max) /Pd (the maximum positive rate ofchange of isovolumic left ventricular pressure divided by the actuallydeveloped pressure in the left ventricle) shows the positive inotropiceffect and T (decrease in the time constant of relaxation) is a measurefor positive lusitropy.

                  TABLE 4                                                         ______________________________________                                        % changes in haemodynamic variables                                           Comp.                                   end-dose                              No.    AoPd     HR      LVdp/dt.sub.max /Pd                                                                     T     mg kg.sup.-1                          ______________________________________                                         2     -10      15      102       -38   0.16                                   6     -13       9      31        -15   0.16                                  11 8   0         0      29        -45   0.16                                  10     -5        0      18        -13   0.16                                  12     0        10      57.5      -10   0.16                                  13     0        -10     45        -27   0.16                                  14     0         5      35        -16   0.08                                  ______________________________________                                    

D. Composition examples

The following formulations exemplify typical pharmaceutical compositionsin dosage unit form suitable for systemic or topical administration towarm-blooded animals in accordance with the present invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

EXAMPLE 27 Oral drops

500 g of the A.I. is dissolved in 0.51 of 2-hydroxypropanoic acid and1.5 l of the polyethylene glycol at 60°-80° C. After cooling to 30°-40°C. there are added 35 l of polyethylene glycol and the mixture isstirred well. Then there is added a solution of 1750 g of sodiumsaccharin in 2.5 l of purified water and while stirring there are added2.5 l of cocoa flavor and polyethylene glycol q.s. to a volume of 50 l,providing an oral drop solution comprising 10 mg/ml of the A.I. Theresulting solution is filled into suitable containers.

EXAMPLE 28 Oral solution

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate aredissolved in 4 l of boiling purified water. In 3 l of this solution aredissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20g of the A.I. The latter solution is combined with the remaining part ofthe former solution and 12 l of 1,2,3-propanetriol and 3 l of sorbitol70% solution are added thereto. 40 g of sodium saccharin are dissolvedin 0.5 l of water and 2 ml of raspberry and 2 ml of gooseberry essenceare added. The latter solution is combined with the former, water isadded q.s. to a volume of 20 l providing an oral solution comprising 5mg of the A.I. per teaspoonful (5 ml). The resulting solution is filledin suitable containers.

EXAMPLE 29 Capsules

20 g of the A.I., 6 g sodium sulfate, 56 g starch, 56 g lactose, 0.8 gcolloidal silicon dioxide, and 1.2 g magnesium stearate are vigorouslystirred together. The resulting mixture is subsequently filled into 1000suitable hardened gelatin capsules, each comprising 20 mg of the A.I.

EXAMPLE 30 Film-coated tablets

Preparation of tablet core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90®) in about 200 mlof water. The wet powder mixture is sieved, dried and sieved again. Thenthere are added 100 g microcrystalline cellulose (Avicel®) and 15 ghydrogenated vegetable oil (Sterotex®). The whole is mixed well andcompressed into tablets, giving 10.000 tablets, each comprising 10 mg ofthe active ingredient.

Coating

To a solution of 10 g methyl cellulose (Methocel 60 HG®) in 75 ml ofdenaturated ethanol there is added a solution of 5 g of ethyl cellulose(Ethocel 22 cps®) in 150 ml of dichloromethane. Then there are added 75ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g ofpolyethylene glycol is molten and dissolved in 75 ml of dichloromethane.The latter solution is added to the former and then there are added 2.5g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml ofconcentrated colour suspension (Opaspray K-1-2109®) and the whole ishomogenated. The tablet cores are coated with the thus obtained mixturein a coating apparatus.

EXAMPLE 31 Injectable solution

1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate aredissolved in about 0.5 l of boiling water for injection. After coolingto about 50° C. there are added while stirring 4 g lactic acid, 0.05 gpropylene glycol and 4 g of the A.I. The solution is cooled to roomtemperature and supplemented with water for injection q.s. ad 1 lvolume, giving a solution of 4 mg A.I. per ml. The solution issterilized by filtration (U.S.P. XVII p. 811) and filled in sterilecontainers.

EXAMPLE 32 Suppositories

3 g A.I. is dissolved in a solution of 3 g 2,3-dihydroxybutanedioic acidin 25 ml polyethylene glycol 400. 12 g surfactant (SPAN®) andtriglycerides (Witepsol 555®) q.s. ad 300 g are molten together. Thelatter mixture is mixed well with the former solution. The thus obtainedmixture is poured into moulds at a temperature of 37°-38° C. to form 100suppositories each containing 30 mg of the A.I.

EXAMPLE 33 Injectable solution

60 g of A.I. and 12 g of benzylalcohol are mixed well and sesame oil isadded q.s. ad 1 l, giving a solution comprising 60 mg/ml of A.I. Thesolution is sterilized and filled in sterile containers.

EXAMPLE 34 Injectable solution

350 g of hydroxypropyl-β-cyclodextrin is dissolved in 2.8 l of water.There are added successively 80.5 g of hydrochloric acid 0.1N and 1.75 gof(E)-N-cyclohexyl-N-methyl-2-[[[phenyl-(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]-quinazolin-7-yl)methylene]-amino]oxy]acetamide.The whole is stirred until a clear solution is obtained and then theacidity is adjusted with sodium hydroxide 1N to pH 6. The solution isdiluted with water to 3.5 l, thus yielding an injectable solutioncontaining 0.5 mg/ml of A.I.

We claim:
 1. A compound having the formula ##STR64## a pharmaceuticallyacceptable addition salt thereof or a stereochemically isomeric formthereof, whereinR is hydrogen, C₁₋₆ alkyl, phenyl optionally substitutedwith from 1 to 3 substituents each independently selected from halo,hydroxy, C₁₋₆ alkyloxy, C₁₋₆ alkyl or trifluoromethyl; pyridinyl; orthienyl optionally substituted with halo or C₁₋₆ alkyl; R¹ is hydrogenor C₁₋₆ alkyl; R² is hydrogen, C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl or phenyl;or R¹ and R² taken together may also form a C₁₋₅ alkanediyl radical; Xis a radical of formula

    ═O                                                     (a),

    ═N--O--R.sup.3                                         (b),

or

    ═CH--R.sup.4                                           (c);

R³ is hydrogen, tri(C₁₋₆ alkyl)silyl or C₁₋₆ alkyl optionallysubstituted with COOH, COOC₁₋₄ alkyl, CONR⁵ R⁶ or COOCH₂ CONR⁷ R⁸ ; R⁴is COOH, COOC₁₋₄ alkyl, CONR⁵ R⁶, COOCH₂ CONR⁷ R⁸ or C₁₋₆ alkyloptionally substituted with COOH, COOC₁₋₄ alkyl, CONR⁵ R⁶ or COOCH₂CONR⁷ R⁸ ; R⁵ is hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl, C₁₋₄alkyloxyC₁₋₄ alkyl, hydroxycarbonylC₁₋₄ alkyl, C₁₋₄ alkyloxycarbonylC₁₋₄alkyl; R⁶ is hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl or C₃₋₇ cycloalkyl;or R⁵ and R⁶ taken together with the nitrogen atom to which they areattached may form a pyrrolidinyl, morpholinyl or piperazinyl ring, saidpiperazinyl ring being optionally substituted on the nitrogen atom withC₁₋₄ alkyl or hydroxyC₁₋₄ alkyl; R⁷ and R⁸ each independently arehydrogen, C₁₋₄ alkyl or hydroxyC₁₋₄ alkyl; and L is a reactive leavinggroup.